Insecticidal substituted-2.4-diaminoquinazolines related applications

ABSTRACT

An insecticidal composition comprising, in admixture with an agriculturally acceptable carrier, an insecticidally effective amount of a 2,4-diaminoquinazoline compound of the formula: ##STR1## wherein R 1 , R 2 , R 6 , R 7 , W, X, Y, and Z are as defined herein; methods of using the same; novel 2,4-diaminoquinazolines per se; and intermediates in the preparation thereof.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.08/267,340, filed Jun. 28, 1994, now U.S. Pat. No. 5,534,518 which inturn is a continuation-in-part of U.S. application Ser. No. 08/149,491,filed Nov. 9, 1993 in the names of Henrie et al, which in turn is acontinuation-in-part of U.S. application Ser. No. 08/019,389, filed Feb.18, 1993 in the names of Henrie et al. (now abandoned).

BACKGROUND OF THE INVENTION

This invention relates to quinazoline compounds and compositionscontaining the same which are useful for controlling insects inagricultural crops. Still more particularly, this invention relates tocertain 2,4-diaminoquinazoline compounds and compositions, and their useas insecticides against a variety of insects, including larvae, such asthe tobacco budworm. Numerous of these diaminoquinazoline compoundsemployed herein, and their preparation, have been described in theliterature for use in a variety of fields, but not as insecticides.

SUMMARY OF THE INVENTION

In accordance with the present invention it has been found thatsubstituted-2,4-diaminoquinazolines, and agriculturally acceptable saltsthereof, when present in insecticidally effective amounts, and with asuitable agricultural carrier, are useful as active ingredients in theinsecticidal compositions and methods of this invention. Thesequinazolines may be represented by the following structure: ##STR2##wherein R¹ and R⁶ are independently hydrogen or lower alkyl;

R² and R⁷ are hydrogen, lower alkyl, alkylcarbonyl e.g., --C(═O)CH₃,--C(═O)C(CH₃)₃, or --C(═O)C₁₁ H₂₃ !, lower alkoxycarbonyl e.g.,--C(═O)OC(CH₃)₃ !, lower haloalkylcarbonyl e.g., --C(═O)C₃ F₇ !,alkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₅ or --C(═O)C₂ H₄ OC₂ H₅ !,alkoxyalkoxyalkylcarbonyl (e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₅),alkoxyalkoxyalkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₄ OCH₃ !,arylcarbonyl (e.g., phenylcarbonyl), substituted arylcarbonyl (e.g.,4-chlorophenylcarbonyl), or alkynylcarbonyl e.g., --C(═O)C.tbd.CCH₃ !;

or R¹ and R², taken together, form the group --R⁵ --O--R⁵, wherein R⁵ islower alkylene;

or R¹ and R², taken together, and R⁶ and R⁷ taken together each form thegroup ##STR3## wherein R⁸ and R⁹ are independently straight or branchedchain lower alkyl e.g., --CH₃, --CH(CH₃)₂ !; or

R⁸ and R⁹ taken together with two to five methylene groups form analkylene ring e.g., --(CH₂)₅ --!;

W, Y, and Z are independently hydrogen, halogen, lower alkyl, loweralkoxy, lower haloalkyl, lower haloalkoxy, thienyl or substitutedthienyl, (e.g., with substituents such as lower alkyl, halogen, orhaloalkyl), aroyl or substituted aroyl, (e.g., with substituents such ashydrogen, halogen, haloalkyl, cyano, carboxy, lower alkoxycarbonyl, orphenyl substituted with halogen or lower haloalkyl), cyano, nitro,amino, lower dialkylamino, aryl (e.g., phenyl) or substituted aryl,(e.g., with substituents such as lower alkyl or lower haloalkyl),arylalkyl, arylalkenyl, arylalkynyl, arylthio, arylsulfinyl,arylsulfonyl, arylaminoalkyl, arylalkylamino, arylalkylimino,(aryl)(halo)alkenyl, substituted (aryl)(halo)alkenyl, (e.g., withsubstituents such as hydrogen, halogen, lower alkyl, lower haloalkyl,cyano, carboxy, lower alkylcarbonyl, or aminocarbonyl),(aryl)(alkyl)aminoalkyl, arylalkycarbonylamino, arylalkylthio, orarylthioalkyl; and

X is

(a) hydrogen, halogen, lower alkyl, lower alkoxy, lower haloalkyl, lowerhaloalkoxy, thienyl or substituted thienyl, (e.g., with substituentssuch as lower alkyl, halogen, or haloalkyl), aroyl or substituted aroyl,(e.g., with substituents such as hydrogen, halogen, haloalkyl, cyano,carboxy, lower alkoxycarbonyl, or phenyl substituted with halogen orlower haloalkyl), cyano, nitro, amino, lower dialkylamino, aryl (e.g.,phenyl or naphthyl), arylalkyl, arylalkenyl, arylalkynyl, aryloxy,arylthio, arylsulfinyl, arylsulfonyl, arylaminoalkyl, arylalkylamino,arylalkylimino, (aryl)(halo)alkenyl, or substituted (aryl)(halo)alkenyl,(e.g., with substituents such as hydrogen, halogen, lower alkyl, lowerhaloalkyl, cyano, carboxy, lower alkylcarbonyl, or aminocarbonyl),(aryl)(alkyl)aminoalkyl, or arylalkycarbonylamino; or

(b) substituted aryl, e.g., phenyl! i.e., aryl substituted with one ormore of halogens (e.g., Cl, F), lower alkyl (e.g., --CH₃), lowerhaloalkyl (e.g., --CF₃), lower alkoxy (e.g., --OCH₃), lower alkylthio(e.g., --SC₄ H₉), lower alkylsulfonyl (e.g., --SO₂ C₂ H₅, or --SO₂ C₄H₉), formyl, lower alkoxycarbonyl e.g., --C(═O)OCH₃ !, phenyl or phenylsubstituted with one or more halogens (e.g., Cl, F) or lower haloalkyl(e.g., --CF₃), phenoxy, or phenoxy substituted with one or more halogens(e.g., Cl, F), lower haloalkoxy, lower alkoxyalkyl, carboxy, cyano,nitro, aminocarbonyl, lower alkylcarbonylamino, loweralkylsulfonylamino; or substituted phenyl of the formula ##STR4##wherein R³ is hydrogen; alkyl, (e.g. methyl, 1-methylethyl, n-pentyl, orundecyl); tri(lower alkyl)silylalkyl; (4-halophenyl)lower alkyl;pentahalophenylalkyl; pyridin-2-ylalkyl; or2-(4-alkylsulfonylphenoxy)ethyl; or

(c) substituted aryloxy, e.g., phenoxy! of the formula: ##STR5## whereinV⁴, W⁴, X⁴, Y⁴, and Z⁴ are selected from hydrogen, halogen, (e.g., Cl),or haloalkyl (e.g., --CF₃); or

(d) a benzo-fused oxygen-containing heterocycle of the formula: ##STR6##wherein A and B are independently selected from oxygen, methylene, andcarbonyl, with the proviso that at least one of A or B is oxygen; D ishydrogen, halogen (e.g., Cl, F), lower alkyl (e.g., --CH₃), or lowerhaloalkyl (e.g., --CF₃); and E is hydrogen, hydroxy, or lower alkoxy(e.g., --OCH₃); to form, for example, the heterocycle2,3-dihydro-2,2-dimethylbenzofuran-4-yl,2,3-dihydro-2,2-dimethylbenzofuran-7-yl,6-halo-2,3-dihydro-2,2-dimethylbenzofuran-4-yl,5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-yl, or2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl; or

(e) an arylalkylamino of the formula: ##STR7## (f) anarylthioalkylcarbonylamino of the formula: ##STR8## and agriculturallyacceptable salts thereof.

Agriculturally acceptable salts of the diaminoquinazolines include, butare not limited to, for example, the salts of hydrochloric acid,ethanesulfonic acid, gluconic acid, and pamoic acid.

Of these compounds, among the more preferred ones for use in thecompositions and methods of this invention are those wherein thediaminoquinazolines are of the structure (I) above, and wherein

(a) R¹ is hydrogen, or lower alkyl;

R⁶ is hydrogen;

R² and R⁷ are independently hydrogen, lower alkyl, alkylcarbonyl e.g.,--C(═O)CH₃, --C(═O)C(CH₃)₃, or --C(═O)C₁₁ H₂₃ !, lower alkoxycarbonyle.g., --C(═O)OC(CH₃)₃ !, lower haloalkylcarbonyl e.g., --C(═O)C₃ F₇ !,alkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₅ or --C(═O)C₂ H₄ OC₂ H₅ !,alkoxyalkoxyalkylcarbonyl (e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₅), oralkoxyalkoxyalkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₄ OC2H₄ OCH₃ !;

Y and Z are hydrogen;

W is halogen, (e.g., chlorine), or lower alkyl, (e.g., methyl orisopropyl); and

X is phenyl, or substituted aryl, e.g., phenyl! i.e., aryl substitutedwith one or more of halogens (e.g., Cl, F), lower alkyl (e.g., --CH₃),lower haloalkyl (e.g., --CF₃), lower alkoxy (e.g., --OCH₃), loweralkylthio (e.g., --SC₄ H₉), lower alkylsulfonyl (e.g., --SO₂ C₂ H₅, or--SO₂ C₄ H₉), formyl, lower alkoxycarbonyl e.g., --C(═O)OCH₃ !, phenylor phenyl substituted with one or more halogens (e.g., Cl, F) or lowerhaloalkyl (e.g., --CF₃), phenoxy, or phenoxy substituted with one ormore halogens (e.g., Cl, F), lower haloalkoxy, lower alkoxyalkyl,carboxy, cyano, nitro, aminocarbonyl, lower alkylcarbonylamino, loweralkylsulfonylamino;

or substituted phenyl of the formula ##STR9## wherein R³ is hydrogen;alkyl, (e.g. methyl, 1-methylethyl, n-pentyl, or undecyl); tri(loweralkyl)silylalkyl; (4-halophenyl)lower alkyl; pentahalophenylalkyl;pyridin-2-ylalkyl; or 2-(4-alkylsulfonylphenoxy)ethyl;

(b) R¹ is hydrogen, or lower alkyl;

R⁶ is hydrogen;

R² and R⁷ are independently hydrogen, lower alkyl, alkylcarbonyl e.g.,--C(═O)CH₃, --C(═O)C(CH₃)₃, or --C(═O)C₁₁ H₂₃ !, or lower alkoxycarbonyle.g., --C(═O)OC(CH₃)₃ !, lower haloalkylcarbonyl e.g., --C(═O)C₃ F₇ !,alkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₅, or --C(═O)C₂ H₄ OC₂ H₅ !,alkoxyalkoxyalkylcarbonyl (e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₅), oralkoxyalkoxyalkoxyalkylcarbonyl e.g., -C(═O)CH2OC2H4OC2H40CH3!;

Y and Z are hydrogen;

W is halogen, (e.g., chlorine), or lower alkyl, (e.g., methyl orisopropyl); and

X is aroyl, (e.g., benzoyl or naphthoyl), or substituted aroyl of theformula: ##STR10## wherein V², W², X², Y², and Z² are independentlyselected from hydrogen, halogen, haloalkyl, cyano, carboxy, loweralkoxycarbonyl, and phenyl substituted with halogen or lower haloalkyl;

(c) R¹ is hydrogen, or lower alkyl;

R⁶ is hydrogen;

R² and R⁷ are independently hydrogen, lower alkyl, alkylcarbonyl e.g.,--C(═O)CH₃, --C(═O)C(CH₃)₃, or --C(═O)C₁₁ H₂₃ !, or lower alkoxycarbonyle.g., --C(═O)OC(CH₃)₃ !, lower haloalkylcarbonyl e.g., --C(═O)C₃ F₇ !,alkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₅, or --C(═O)C₂ H₄ OC₂ H₅ !,alkoxyalkoxyalkylcarbonyl (e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₅), oralkoxyalkoxyalkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₄ OCH₃ !;

Y and Z are hydrogen;

W is halogen (e.g., chlorine) or lower alkyl (e.g., methyl orisopropyl); and

X is (aryl)(halo)alkenyl of the formula: ##STR11## wherein V¹, W¹, X¹,Y¹, and Z¹ are independently selected from hydrogen, halogen, loweralkyl, lower haloalkyl, cyano, carboxy, lower alkoxycarbonyl, andaminocarbonyl; and

(d) R¹ is hydrogen, or lower alkyl;

R⁶ is hydrogen;

R² and R⁷ are independently hydrogen, lower alkyl, alkylcarbonyl e.g.,--C(═O)CH₃, --C(═O)C(CH₃)₃, or --C(═O)C₁₁ H₂₃ !, lower alkoxycarbonyle.g., --C(═O)OC(CH₃)₃ !, lower haloalkylcarbonyl e.g., --C(═O)C₃ F₇ !,alkoxyalkylcarbonyl e.g., --C(═O)CH2OC₂ H₅, or --C(═O)C₂ H₄ OC₂ H₅ !,alkoxyalkoxyalkylcarbonyl (e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₅), oralkoxyalkoxyalkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₄ OCH₃ !;

Y and Z are hydrogen;

W is halogen or lower alkyl (e.g., methyl); and

X is a benzo-fused oxygen-containing heterocycle of the formula:##STR12## wherein A and B are independently selected from oxygen,methylene, and carbonyl; with the proviso that at least one of A or B isoxygen; D is hydrogen, halogen (e.g., Cl, F), lower alkyl (e.g., --CH₃),or lower haloalkyl (e.g., --CF₃); and E is hydrogen, hydroxy, or loweralkoxy (e.g., --OCH3); to form, for example, the heterocycle2,3-dihydro-2,2-dimethylbenzofuran-4-yl,2,3-dihydro-2,2-dimethylbenzofuran-7-yl,6-halo-2,3-dihydro-2,2-dimethylbenzofuran-4-yl,5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-yl, or2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl.

Other compounds of particular interest falling within the scope of thisinvention include compounds of Formula I wherein

(i) R¹, R², R⁶, and R⁷ are hydrogen;

Y and Z are hydrogen;

W is hydrogen, halogen, (e.g., chlorine), or lower alkyl, (e.g.,methyl);

X is arylaminoalkyl or arylalkylimino of the formula: ##STR13## whereinQ is alkylimino of the formula --N═CH-- (in which the left-hand portionof the moiety Q is attached to the quinazoline ring), or aminoalkyl ofthe formula --CH₂ NH--;

n is 1, 2, or 3;

m is 0 or 1; and

R⁴ is hydrogen or lower alkyl;

with the proviso that when m is 0, R⁴ must be hydrogen, and n must be 1;and

(ii) R¹, R², R⁶, and R⁷ are hydrogen;

W, Y, and Z are hydrogen; and

X is an (aryl)(alkyl)aminoalkyl of the formula: ##STR14##

In a further embodiment, this invention is also directed to certainnovel substituted quinazolines per se falling within the scope offormula (I) above. These compounds, as illustrated by Compounds 43-45,47-74, 106-138, 142-173, and 176-182 of Table I below, include thefollowing novel quinazolines, which may be prepared by methods that areprovided in detail in Examples 1-3, 5, and 16-19: ##STR15## wherein R¹is hydrogen, or lower alkyl;

R⁶ is hydrogen;

R² and R⁷ are independently hydrogen, lower alkyl, alkylcarbonyl e.g.,--C(═O)CH₃, --C(═O)C(CH₃)₃, or --C(═O)C₁₁ H₂₃ !, lower alkoxycarbonyle.g., --C(═O)OC(CH₃)₃ !, lower haloalkylcarbonyl e.g., --C(═O)C₃ F₇ !,alkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₅, or --C(═O)C₂ H₄ OC₂ H₅ !,alkoxyalkoxyalkylcarbonyl (e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₅), oralkoxyalkoxyalkoxyalkylcarbonyl e.g., --C(═O)CH₂ OC₂ H₄ OC₂ H₄ OCH₃ !;or R¹ and R², taken together, form the group --R⁵ --O --R⁵, wherein R⁵is lower alkylene;

W is selected from hydrogen, halogen, lower alkyl, lower haloalkyl,phenyl, and phenyl substituted with lower alkyl or lower haloalkyl, withthe proviso that when X is phenyl, W is other than hydrogen;

Y and Z are selected from hydrogen, halogen, and phenyl; and

X is selected from

(a) phenyl;

(b) substituted aryl, e.g., phenyl! i.e., aryl substituted with one ormore of halogens (e.g., Cl, F), lower alkyl (e.g., --CH₃), lowerhaloalkyl (e.g., --CF₃), lower alkoxy (e.g., --OCH₃), lower alkylthio(e.g., --SC₄ H₉), lower alkylsulfonyl (e.g., --SO₂ C₂ H₅, or --SO₂ C₄H₉), formyl, lower alkoxycarbonyl e.g., --C(═O)OCH₃ !, phenyl or phenylsubstituted with one or more halogens (e.g., Cl, F) or lower haloalkyl(e.g., --CF₃), phenoxy, or phenoxy substituted with one or more halogens(e.g., Cl, F), lower haloalkoxy, lower alkoxyalkyl, carboxy, cyano,nitro, aminocarbonyl, lower alkylcarbonylamino, loweralkylsulfonylamino;

or substituted phenyl of the formula ##STR16## wherein R³ is hydrogen;alkyl, (e.g. methyl, 1-methylethyl, n-pentyl, or undecyl); tri(loweralkyl)silylalkyl; (4-halophenyl)lower alkyl; pentahalophenylalkyl;pyridin-2-ylalkyl; or 2-(4-alkylsulfonylphenoxy)ethyl;

(c) naphthyl;

(d) thienyl or thienyl substituted with halogen, lower alkyl, orhaloalkyl;

(e) aroyl or substituted aroyl of the formula: ##STR17## wherein V², W²,X², Y², and Z² are independently selected from hydrogen, halogen,haloalkyl, cyano, carboxy, lower alkoxycarbonyl, and phenyl substitutedwith halogen or haloalkyl;

(f) (aryl)(halo)alkenyl of the formula: ##STR18## wherein V¹, W¹, X¹,Y¹, and Z¹ are independently selected from hydrogen, halogen, loweralkyl, lower haloalkyl, cyano, carboxy, lower alkoxycarbonyl, andaminocarbonyl; and

(g) is a benzo-fused oxygen-containing heterocycle of the formula:##STR19## wherein A and B are independently selected from oxygen,methylene, and carbonyl; with the proviso that at least one of A or B isoxygen; D is hydrogen, halogen (e.g., Cl, F), lower alkyl (e.g., --CH₃),or lower haloalkyl (e.g., --CF₃); and E is hydrogen, hydroxy, or loweralkoxy (e.g., --OCH₃); to form, for example, the heterocycle2,3-dihydro-2,2-dimethylbenzofuran-4-yl,2,3-dihydro-2,2-dimethylbenzofuran-7-yl,6-halo-2,3-dihydro-2,2-dimethylbenzofuran-4-yl,5-halo-2,3-dihydro-2,2-diemthylbenzofuran-7-yl, or2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl.

Preferred amongst the above novel quinazolines are those of Formula IXwherein R¹, R², R⁶, R⁷, Y and Z are hydrogen; W is methyl; and X is

(i) phenyl substituted with one or more of fluoro, chloro, ortrifluoromethyl;

(ii) compounds of the formula ##STR20## wherein V¹, W¹, X¹, Y¹, and Z¹are independently selected from hydrogen, chloro, and trifluoromethyl;or

(iii) a benzo-fused oxygen containing heterocycle of the formula:##STR21## wherein A and B are independently selected from oxygen,methylene, and carbonyl; with the proviso that at least one of A or B isoxygen; D is hydrogen, halogen (e.g., Cl, F), lower alkyl (e.g., --CH₃),or lower haloalkyl (e.g., --CF₃); and E is hydrogen, hydroxy, or loweralkoxy (e.g., --OCH₃); to form, for example, the heterocycle2,3-dihydro-2,2-dimethylbenzofuran-4-yl,2,3-dihydro-2,2-dimethylbenzofuran-7-yl,6-halo-2,3-dihydro-2,2-dimethylbenzofuran-4-yl,5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-yl, or2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl.

Each of the above novel substituted phenyl quinazoline compounds per sefalling within the scope of Formula (I) are preferred because of theirhigh insecticidal activity, and thus may be used in controlling insectsby applying to the locus where control is desired an insecticidal amountof these compounds admixed in a suitable agricultural carrier. Whenapplied to insect-infected crops such as cotton, vegetables, fruits orother crops, these compounds are highly effective against an array ofinsects, particularly those shown in the tables below.

For the purposes of this invention, as regards the above substituentgroups, the following definitions apply:

The term alkyl, alone or as part of a larger moiety, includes straightor branched chained alkyl groups of 1 to 14 carbon atoms, preferablylower straight or branched alkyl of 1 to 6 carbon atoms; while halogenincludes chlorine, bromine, fluorine and iodine atoms. The termshaloalkyl and haloalkoxy include straight or branched chain alkyl of 1to 14 carbon atoms, preferably lower straight or branched alkyl of 1 to6 carbon atoms, wherein one or more hydrogen atoms have been replacedwith halogen atoms, as, for example, trifluoromethyl and2,2,2-trifluoroethoxy, respectively. The terms lower alkoxy and lowerdialkylamino include those moieties having 1 to 6 carbon atoms, e.g.,ethoxy and N,N-dimethylamino, respectively.

The terms aryl and substituted aryl include phenyl and naphthyl,preferably phenyl or substituted phenyl, while the terms aroyl andsubstituted aroyl include benzoyl and naphthoyl, preferably benzoyl orsubstituted benzoyl.

The term "substituted" as described above, when applied to thesubstituted aryl, aroyl, and thienyl moieties of W, X, Y, and Z informula I, above, includes such substituents as lower alkyl, halogen,lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkoxyalkyl,carboxy, lower alkoxycarbonyl, cyano, nitro, aminocarbonyl, loweralkylsulfonyl, lower alkylcarbonylamino, lower alkylsulfonylamino, loweralkylthio, lower alkylsulfonyl, formyl, lower alkoxycarbonyl, phenyl,phenyl substituted with one or more halogens or lower haloalkyl,phenoxy, phenoxy substituted with one or more halogens, arylalkoxy,arylalkoxy substituted with halogen or lower alkyl, aryloxyalkoxy,aryloxyalkoxy substituted with lower alkylsulfonyl, or lower alkyl, ordialkylsilylalkoxy.

Groups other than aryl, aroyl, and thienyl which may also be substitutedinclude arylalkylamino or arylaminoalkyl (where the aryl groups may besubstituted with e.g., lower alkoxy or carboxyalkoxy); arylalkylimino(where the aryl group may be substituted with, e.g., lower alkoxy);arylalkycarbonylamino (where the aryl group may be substituted with,e.g. halogen); (aryl)(alkyl)aminoalkyl (where the aryl group may besubstituted with, e.g. dicarboxyalkylaminocarbonyl); and(aryl)(halo)alkenyl (where the aryl group may be substituted withhalogen, lower alkyl, lower haloalkyl, cyano, carboxy, loweralkoxycarbonyl, or aminocarbonyl).

Illustrations of the substituted phenyl groups further include suchmoieties as: ##STR22## wherein R³ is hydrogen; alkyl, (e.g. methyl,1-methylethyl, n-pentyl, or undecyl); tri(lower alkyl)silylalkyl;(4-halophenyl)lower alkyl; pentahalophenylalkyl; pyridin-2-ylalkyl; or2-(4-alkylsulfonylphenoxy)ethyl, or the like.

In addition, the term arylalkyl includes 2-(naphth-2-yl)ethyl;arylalkenyl includes 2-(naphth-2-yl)ethenyl; arylthio includes3,4-dichlorophenylthio and naphth-2-ylthio; arylsulfinyl includes3,4-dichlorophenylsulfinyl and naphth-2-ylsulfinyl; while arylsulfonylincludes 3,4-dichlorophenylsulfonyl and naphth-2-ylsulfonyl.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of The Compounds

The compounds employed as insecticides in accordance with this inventionare generally known to those skilled in the art, including commercialpreparations thereof, or may readily be prepared from these compounds byknown methods. These and other methods are described in further detailin the description and examples below.

Thus, in general, the majority of the quinazoline products (formula Iabove) can be prepared by the cyclization of the appropriatelysubstituted 2-aminobenzonitrile with chloroformamidine hydrochloride indiglyme, as taught by Harris et al, J. Med. Chem., 33, 434-444 (1990)!and as further shown in Step 1 of Example 1, below. The starting2-aminobenzonitriles are also generally available commercially, but maybe prepared in accordance with the processes taught in each of Examples2, 6, and 20-26. In these examples, the desired 2-aminobenzonitrilestarting materials substituted with halogen may be prepared by thereaction of either 2-aminobenzonitrile, 2-amino-5-chlorobenzonitrile, or2-amino-6-chlorobenzonitrile with 1 or 2 equivalents ofN-bromosuccinimide or 1 equivalent of N-chlorosuccinimide inN,N-dimethylformamide. Intermediates prepared by this method include thefollowing benzonitriles: ##STR23## wherein, alternatively, X and Z areBr;

X is Br;

X is Cl, and Z is Br;

X and Z are Cl;

W is Cl, and X is Br;

X is Br, and Z is Cl; or

W is Cl, and X and Z are Br;

with the proviso that unless otherwise specified, W, X, Y, and Z arehydrogen.

The halogenated 2-aminobenzonitrile intermediates thus prepared may thenbe either reacted to prepare the quinazolines (I) as previouslydescribed, or used to prepare other substituted 2-aminobenzonitrileintermediates, as described below.

For example, 2-amino-5-bromo-6-chlorobenzonitrile, or2-amino-3,5-dibromobenzonitrile, can be further reacted with 1 or 2equivalents of an optionally substituted-phenylboronic acid in thepresence of tetrakis(triphenylphosphine)palladium(0) in aqueous sodiumcarbonate and toluene to form more complex substituted2-aminobenzonitrile intermediates (B), as listed below. Substituted2-aminobenzonitrile intermediates (B) prepared in this manner include,for example, 2-amino-6-chloro-5-(5-chloro-2-methoxyphenyl)benzonitrileand 2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrile. Theseoptionally substituted-phenylboronic acid intermediates are commerciallyavailable, or may be prepared by the method of Thompson and GaudinoJOC., 49, 5237-5243 (1984)!. Step D of Example 1, Steps B-D of Example2, and Step A of Example 5 provide detailed descriptions of how thesereactions may be conducted.

Intermediates prepared by this foregoing method include those of theformula: ##STR24## wherein Y is hydrogen and W, X and Z are as definedin the following table:

    ______________________________________    W             X                Z    ______________________________________    H             Phenyl           Phenyl    H             Phenyl           H    H             Cl               Phenyl    H             Phenyl           Cl    Cl            Phenyl           H    Cl            Phenyl           Phenyl    Cl                   ##STR25##       H    Cl                   ##STR26##       H    Cl                   ##STR27##       H    Cl                   ##STR28##       H    Cl                   ##STR29##       H    Cl                   ##STR30##       H                   ##STR31##       H    H                   ##STR32##       H    Cl                   ##STR33##       H     ##STR34##                   ##STR35##       H    Cl                   ##STR36##       H    ______________________________________

Alternatively, 2-aminobenzonitrile intermediates substituted with alkylmay be prepared by the method of Harris et al., J. Med. Chem., 33,434-444 (1990) by the transfer hydrogenation of the alkyl-substituted2-nitrobenzonitrile in the presence of 10% palladium on carbon incyclohexene and ethanol, yielding the corresponding alkyl-substituted2-aminobenzonitrile, for example, 6-methyl-2-aminobenzonitrile. Thethus-prepared 6-methyl-2-aminobenzonitrile may then be halogenated withN-bromosuccinimide or N-iodosuccinimide in N,N-dimethylformamide,yielding the corresponding 2-amino-5-halo-6-methylbenzonitrile, which inturn can be reacted with 1 equivalent of, for example, asubstituted-phenylboronic acid or a benzo-fused oxygen-containingheterocyclylboronic acid, affording the corresponding2-amino-5-substituted-6-methylbenzonitrile, for example, 2-amino-5-3,5-di(trifluoromethyl)phenyl!-6-methylbenzonitrile, or2-amino-5-(2,3-dihydro-2,2,6-trimethyl-benzofuran-4-yl)-6-methylbenzonitrile.Steps B-D of Example 1, Step A of Example 17, and Steps A-F of Example30 provide detailed descriptions of how these intermediates may beprepared.

Intermediates prepared by these latter methods include those having theformula: ##STR37## wherein Y and Z are hydrogen, and W and X are asfollows:

    ______________________________________    W         X    ______________________________________    CH.sub.3               ##STR38##    CH.sub.3               ##STR39##    CH.sub.3               ##STR40##    CH.sub.3               ##STR41##    CH.sub.3  Phenyl    CH.sub.3               ##STR42##    CH.sub.3               ##STR43##    CH.sub.3               ##STR44##    CH.sub.3               ##STR45##    CH.sub.3               ##STR46##    CH.sub.3               ##STR47##      Other intermediates, as well as the qunizaoline products falling within    formula (I) above and Table I below, may be prepared from the foregoing    or analogous compounds by these or analogous methods known to those

For example, the 2-aminobenzonitrile intermediate,2-amino-5-(2-phenylethyl)benzonitrile, may be prepared using the methodof Taylor and Ray JOC., 52, 3997-4000 (1987)!, by thepalladium-catalyzed coupling of 2-amino-5-bromobenzonitrile withphenylacetylene, yielding 2-amino-5-(2-phenylethynyl)benzonitrile. Thethus-prepared ethynyl compound can then be hydrogenated in the presenceof 10% palladium on carbon, yielding2-amino-5-(2-phenylethyl)benzonitrile. Steps B and C of Example 6provide a detailed description of how these reactions are conducted.

Other 2-aminobenzonitrile intermediates substituted with asulfurbridging moiety, for example, naphth-2-ylthio, may be prepared bythe method of Ashton and Hynes J. Med. Chem., 16, 1233-1237 (1973)! bythe alkylation of an appropriate arylthiol with a halogenated2-nitrobenzonitrile in the presence of potassium carbonate, yielding,for example, 2-nitro-5-(naphth-2-ylthio)benzonitrile. Reduction of thenitro group with stannous chloride dihydrate affords the corresponding2-aminobenzonitrile intermediates. Examples 7 and 9 provide detaileddescriptions of how these reactions are conducted.

A number of the quinazolines (I), or modifications thereof, may befurther reacted to obtain other quinazoline derivatives falling withinthe scope of formula I above. For example,2,4,6-triamino-5-methylquinazoline is prepared in a step-wise manner bythe nitration of 2-chloro-6-methylbenzonitrile, yielding thecorresponding 2-chloro-6-methyl-5-nitrobenzonitrile. The 5-nitrocompound may in turn be cyclyzed with guanidine carbonate in2-ethoxyethanol, affording 2,4-diamino-5-methyl-6-nitroquinazoline.These two steps of the synthesis are described in detail in Example 12.The 6-nitroquinazoline can be reduced to the corresponding2,4,6-triamino-5-methylquinazoline by hydrogenation in the presence of10% palladium on carbon. Example 13 describes in detail this step in thereaction sequence.

In a similar manner 2,4,6-triaminoquinazoline and2,4,6-triamino-5-chloroquinazoline can be prepared. This is accomplishedby the nitration of, for example, 2,4-diamino-5-chloroquinazoline(above) with 90% nitric acid and sulfuric acid, yielding thecorresponding 2,4-diamino-5-chloro-6-nitroquinazoline. The6-nitroquinazoline is in turn reduced by either hydrogenation in thepresence of 10% palladium on carbon or by treatment with stannouschloride dihydrate, affording the corresponding2,4,6-triaminoquinazoline. Steps A and B of Example 15 describe indetail these two steps in the reaction sequence.

The 2,4,6-triaminoquinazoline derivatives described above may thenoptionally be treated with 2N hydrochloric acid, sodium nitrite,potassium cyanide, and copper(II) sulfate pentahydrate in water,affording the corresponding 2,4-diamino-6-cyanoquinazoline, for example,2,4-diamino-6-cyano-5-methylquinazoline. Step A of Example 14 describesin detail this step in the reaction sequence.

The above 2,4-diamino-6-cyanoquinazoline intermediates may be furtherreacted with a substituted aniline, for example,3,4,5-trimethoxyaniline, and hydrogen in the presence of Raney nickel inwater and acetic acid, affording the corresponding2,4-diamino-6-(substituted-aminomethyl)quinazolines. Step B of Example14 describes in detail the preparation of this class of compounds.

In a similar manner, 2,4,6-triamino-5-chloroquinazoline can be reactedwith 3,4,5-trimethoxybenzaldehyde and hydrogen in the presence of Raneynickel in 2-ethoxyethanol, affording the corresponding 2,4-diamino-6-(3,4,5-trimethoxyphenylmethyl)imino!quinazoline. Step C of Example 15describes in detail the preparation of this compound. In a similarmanner there may also be prepared2,4-diamino-6-(substituted-aminomethyl)quinazolines.

A series of quinazoline analogs may be prepared from the above2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline. This isaccomplished by the reaction of2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline with 1Mboron tribromide in methylene chloride, yielding the corresponding2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline. Thehydroxy intermediate in turn is reacted with a halogen-containingcompound and potassium carbonate in N,N-dimethylformamide, affording theappropriately 6-(5-chloro-2-substituted-phenyl)quinazoline, for example,2,4-diamino-5-chloro-6-5-chloro-2-(pyridin-2-ylmethoxy)phenyl!quinazoline. Example 3 describesin detail the preparation of this compound.

Other like analogs of quinazoline may be prepared in a similar manner.Quinazoline derivatives containing a sulphur bridge, for example thosewhose preparations are taught in Examples 7 and 9, can be oxidized tothe corresponding sulfinyl derivatives using the method of Oae et al.,Bull. Chem. Soc. Japan, 39, 364-366 (1966)!, by the treatment of, forexample, 2,4-diamino-6-(3,4-dichlorophenylthio)quinazoline with thebromine complex of 1,4-diazabicyclo(2,2,2)-octane in aqueous 70% aceticacid. Example 11 describes in detail the preparation of2,4-diamino-6-(3,4-dichlorophenylsulfinyl)quinazoline. The correspondingsulfonyl derivatives may then be prepared by treatment of these sulfurbridged quinazolines with potassium permanganate in acetic acid andwater. Examples 8 and 10 describe in detail the preparation of thesecompounds.

Compounds of formula (I) above, wherein the 2,4-diamino moieties aresubstituted, e.g., Compounds 272-274 of Table 1, may be prepared by thereaction of a 2,4-diaminoquinazoline with an appropriately substitutedformamidine dimethyl acetal, for example, dimethylformamidine dimethylacetal, yielding the corresponding 2,4-di(substituted-amino)quinazoline,for example, 2,4-di(dimethylaminomethyleneamino)-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline. Example 28 describes indetail the preparation of these compounds.

Other 2,4-di(substituted-amino) compounds, e.g., Compounds 215-217 and251-271 of Table 1, may also be prepared by the reaction of a2,4-diaminoquinazoline with other reactants, such as an appropriatelysubstituted anhydride, for example, 3,6,9-trioxadecanoic anhydride,under basic conditions in the presence of dimethylaminopyridine,yielding the corresponding 2,4-di(substituted-ami no)quinazoline, forexample, 2,4-di(1-oxo-3,6,9-trioxadecaneamino)-5-methyl-6-3,5-di(trifluoromethyl)phenyl!-quinazoline. Example 32 describes indetail the preparation of these compounds.

Compounds of formula (I) above, wherein X is aroyl or substituted aroyl,e.g. Compounds 149-173 of Table 1, may be prepared in a step-wise mannerusing methods known from the open literature. Using the method ofBeletskaya et al., (Bumagin et. al., Dokl. Akad. Nauk SSSR, 320(3),619-622 (1991)) an appropriately substituted aryl iodide, for example,2-amino-5-iodo-6-methylbenzonitrile, may be carbonylated under about oneatmosphere of pressure with carbon monoxide and tetramethylammoniumtetra(optionally-substituted-phenyl)borate in the presence of acatalytic amount of palladium acetate, yielding the correspondingketone, for example,2-amino-5-(4-trifluoromethylphenylcarbonyl)-6-methylbenzonitrile. Theketone may then be cyclized with chloroformamidine hydrochloride in2-methoxyethyl ether, a method previously described, affording thetargeted quinazoline derivative, for example,2,4-diamino-5-methyl-6-(4-trifluoromethylphenylcarbonyl)quinazoline.Example 19, discusses in detail this reaction sequence. Compounds offormula (I) above, wherein X is substituted aryloxy. e.g., Compounds242-250 of Table 1, may also be prepared in a step-wise manner. Forexample, the sodium salt of an appropriately substituted phenol may bereacted with 5-chloro-2-nitrobenzonitrile, yielding the corresponding5-(substituted-phenoxy)-2-nitrobenzonitrile. The so-prepared2-nitrobenzonitrile may then be reduced with iron powder andhydrochloric acid in water and ethanol, affording2-amino-5-(substituted-phenoxy)benzonitrile. The 2-aminobenzonitrile maythen be cyclized with chloroformamidine hydrochloride in 2-methoxyethylether, a method previously described, affording the targeted quinazolinederivative, for example, 2,4-diamino-6-(4-chlorophenoxy)quinazoline.Example 28, discusses in detail this reaction sequence.

Compounds where X is arylalkylcarbonylamino, e.g., Compounds 174 and 175of Table 1, may be prepared, by the reaction of a2,4,6-triaminoquinazoline, for example,2,4,6-triamino-5-chloroquinazoline (Compound 24) with an appropriatearylalkylcarbonyl halide under basic conditions, or they may be obtainedcommercially from Dr. John B. Hynes, Dept. of Pharmaceutical Sciences,Medical University of South Carolina, 171 Ashley Avenue, Charleston,S.C. 29425-2303.

Agriculturally acceptable salts, e.g., Compounds 275-278 of Table 1, maybe prepared by methods known to those skilled in the art.

EXAMPLES

The following examples, which disclose the preparation of representativecompounds of this invention (Table 1), are for the purpose ofillustrating known methods for the preparation of the compounds employedin the methods and formulations of this invention, including certainnovel quinazoline compounds per se (Compounds 43-45, 47-74, 106-138,142-173, and 176-284).

Example 1

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-3,5-DI(TRIFLUOROMETHYL)PHENYL!QUINAZOLINE (COMPOUND 63)

Step A Synthesis of chloroformamidine hydrochloride as an intermediate

Diethyl ether, 600 mL, was cooled in an ice-bath and saturated withabout 50 grams of hydrogen chloride gas. With vigorous stirring, asolution of 26.4 grams (0.628 mole) of cyanamide in 500 mL of diethylether was added during a 15 minute period. Upon completion of addition,the ice-bath was removed and the reaction mixture was allowed to stirfor about 15 minutes. A white, solid precipitate was collected byfiltration and washed with diethyl ether. The solid was dried underreduced pressure, yielding 50.3 grams of chloroformamidinehydrochloride.

Step B Synthesis of 2-amino-6-methylbenzonitrile as an intermediate

A stirred solution of 13.8 grams (0.085 mole) of2-methyl-6-nitrobenzonitrile, 28 mL of cyclohexene, and 1.5 gram of 10%palladium on charcoal in 280 mL of ethanol was heated at reflux forabout 3 hours. After this time, the reaction mixture was filtered toremove the catalyst. The filtrate was concentrated under reducedpressure to a solid residue. The solid was triturated with 50 mL ofmethylene chloride, and the insoluble material was collected byfiltration. Upon standing, crystals formed in the filtrate. The crystalswere collected by filtration and were washed quickly with a minimumamount of methylene chloride. An NMR spectrum of the crystals, 2.3grams, mp 125°-126° C., indicated that they were sought-after product. Asecond crop of product, 1.8 grams, was collected from the methylenechloride-filtrate combination. The insoluble material from thetrituration was dissolved in methylene chloride and methanol and passedthrough a pad of diatomaceous earth. The filtrate was concentrated underreduced pressure, yielding 4.5 grams of solid. The NMR spectrum of thesolid indicated that it too was the sought-after product. The totalyield of 2-amino-6-methylbenzonitrile was about 8.6 grams.

Step C Synthesis of 2-amino-5-bromo-6-methylbenzonitrile as anintermediate

A stirred solution of 8.3 grams (0.063 mole) of2-amino-6-methylbenzonitrile in 125 mL of N,N-dimethylformamide wascooled in an ice bath, and a solution of 11.2 grams (0.063 mole) ofN-bromosuccinimide in 125 mL of N,N-dimethylformamide was added dropwiseduring a 30 minute period, while maintaining the reaction mixturetemperature at about 15°-25° C. Upon completion of addition, thereaction mixture was stirred at ambient temperature for about 20 hours.After this time, the reaction mixture was poured into 1 liter of aqueous3N sodium hydroxide. The mixture was then diluted to a volume of about1700 mL with distilled water. A solid precipitate was collected byfiltration and dried under reduced pressure, yielding 12.3 grams of2-amino-5-bromo-6-methylbenzonitrile, mp 111°-113° C. The NMR spectrumwas consistent with the proposed structure.

Step D Synthesis of 2-amino-6-methyl-5-3,5-di(trifluoromethyl)phenyl!-benzonitrile as an intermediate

A stirred solution of 1.7 grams (0.008 mole) of2-amino-5-bromo-6-methylbenzonitrile, 3.2 grams (0.012 mole) of3,5-di(trifluoromethyl)-phenylboronic acid, 4.3 grams (0.031 mole) ofpotassium carbonate and 0.3 mL oftetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene was heatedat 90° C. for about 20 hours. After this time, the reaction mixture wasstirred with 100 mL of water, and the organic layer was separated. Theorganic layer was concentrated under reduced pressure to a residue. Theresidue was subjected to column chromatography on silica gel, using30/65/5 and 20/60/20 methylene chloride/petroleum ether/ethyl acetate aseluants. The product-containing fractions were combined and concentratedunder reduced pressure, yielding about 1.0 gram of 2-amino-6-methyl-5-3,5-di(trifluoromethyl)phenyl!benzonitrile. The NMR spectrum wasconsistent with the proposed structure.

Step E Synthesis of 2,4-diamino-6-methyl-5-3,5-di(trifluoromethly)-phenyl!quinazoline (Compound 63)

A stirred mixture of 0.9 gram (0.003 mole) of 2-amino-6-methyl-5-3,5-di(trifluoromethyl)phenyl!benzonitrile and 0.3 gram (0.003 mole) ofchloroformamidine hydrochloride (prepared in Step A of this Example) in11 mL of 2-methoxyethyl ether was gradually warmed to 165° C. during a1.5 hour period. The heterogeneous mixture was maintained at 165° C. forabout 4.5 hours. After this time, the reaction mixture was cooled anddiluted with 200 mL of diethyl ether. The resultant precipitate, whichwas the hydrochloride salt of the sought-after product, was collected byfiltration. The hydrochloride salt was recrystallized from n-propanoland water. The solid was converted to the free base by cooling it in anice-water bath and stirring it with 30 mL of concentrated ammoniumhydroxide during a one hour period. The resultant solid was collected byfiltration, yielding 0.4 gram of 2,4-diamino-6-methyl-5-3,5-di(trifluoromethyl)phenyl!quinazoline, mp 222°-225° C. The NMRspectrum was consistent with the proposed structure.

NOTE: The compound of Example 1 was prepared by the method of Harris etal, J. Med. Chem., 33, 434-444 (1990)!

Example 2

SYNTHESIS OF2,4-DIAMINO-5-CHLORO-6-(5-CHLORO-2-METHOXYPHENYL)QUINAZOLINE (COMPOUND66)

Step A Synthesis of 2-amino-5-bromo-6-chlorobenzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 18.0 grams (0.010 mole) of N-bromosuccinimide, and 15.2grams (0.010 mole) of 2-amino-6-chlorobenzonitrile in 200 mL ofN,N-dimethylformamide. The yield of 2-amino-5-bromo-6-chlorobenzonitrilewas 22.5 grams. The NMR spectrum was consistent with the proposedstructure

Step B Synthesis of 3-bromo-4-methoxychlorobenzene as an intermediate Arapidly stirred solution of 15.5 grams (0.074 mole) of2-bromo-4-chlorophenol, 20.0 grams (0.145 mole) of anhydrous powderedpotassium carbonate, and 10 mL (0.106 mole) of dimethyl sulfate in 150mL of acetone was heated at reflux for about 18 hours. After this time,the reaction mixture was concentrated under reduced pressure to aresidue. The residue was partitioned between 100 mL each of water andmethylene chloride. The organic layer was removed and washed with anaqueous solution saturated with sodium chloride. The organic layer wasthen dried with magnesium sulfate and filtered. The filtrate was passedthrough a short column of silica gel. Elution was accomplished with 500mL of methylene chloride. The eluate was concentrated under reducedpressure, yielding 16.3 grams of 3-bromo-4-methoxychlorobenzene. The NMRspectrum was consistent with the proposed structure.

Step C Synthesis of 5-chloro-2-methoxyphenylboronic acid as anintermediate

A stirred solution of 5.8 grams (0.026 mole) of3-bromo-4-methoxychlorobenzene in 150 mL of tetrahydrofuran was cooledto -80° C., and 11.5 mL of n-butyllithium in hexanes (2.5 Molar-0.029mole) was added dropwise during a 15 minute period, while maintainingthe reaction mixture temperature at about -70° C. The initial reactionwas very exothermic, which required cooling the reaction mixture toabout -100° C. Upon completion of the addition, the reaction mixture wasstirred at -80° C. for 15 minutes. After this time, 17.5 mL (0.076 mole)triisopropyl borate was added during a 1 minute period. The reactionmixture was then allowed to warm slowly to ambient temperature during a3 hour period, where it was stirred for an additional 1 hour. After thistime, the reaction mixture was concentrated under reduced pressure to avolume of about 50 mL. The concentrate was then poured into 500 mL ofice-water. The mixture was then made acidic with about 26 mL of aqueous2N hydrochloric acid. The mixture was then filtered to collect a solid,which was dried, yielding 3.9 grams of 5-chloro-2-methoxyphenylboronicacid. The NMR spectrum was consistent with the proposed structure.

NOTE: A modification of the method of Thompson and Gaudino was used toprepare 5-chloro-2-methoxyphenylboronic acid, as shown above in Step C.JOC., 49, 5237-5243 (1984)!

Step D Synthesis of2-amino-6-chloro-5-(5-chloro-2-methoxyphenyl)benzonitrile as anintermediate

A stirred mixture of 5.7 grams (0.020 mole) of5-chloro-2-methoxyphenylboronic acid, 3.3 grams (0.014 mole) of2-amino-5-bromo-6-chlorobenzonitrile (prepared in Step A of thisExample), 21 mL of aqueous 2M sodium carbonate, and 0.15 gram (catalyst)of tetrakis(triphenylphosphine)palladium(0) in 50 mL of toluene washeated at reflux for about 17 hours. After this time, 50 mL of ethylacetate was added to the reaction mixture. The organic layer wasseparated and washed with 50 mL of water and then with 50 mL of anaqueous solution saturated with sodium chloride. The organic layer wasthen dried with magnesium sulfate and filtered. The filtrate wasconcentrated under reduced pressure to a residue. The residue wassubjected to column chromatography on silica gel. Elution wasaccomplished using methylene chloride. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 3.8grams of 2-amino-6-chloro-5-(5-chloro-2-methoxyphenyl)benzonitrile. TheNMR spectrum was consistent with the proposed structure.

Step E Synthesis of2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline (Compound66)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 3.8 grams (0.013 mole) of2-amino-6-chloro-5-(5-chloro-2-methoxyphenyl)benzonitrile and 1.8 grams(0.016 mole) of chloroformamidine hydrochloride in 13 mL of2-methoxyethyl ether. The yield of2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline was 2.8grams. The NMR spectrum was consistent with the proposed structure.

Example 3

SYNTHESIS OF 2,4-DIAMINO-5-CHLORO-6-5-CHLORO-2-(PYRIDIN-2-YLMETHOXY)PHENYL!QUINAZOLINE (COMPOUND 73)

Step A Synthesis of2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline (Compound65) as an intermediate

A solution of 2.8 grams (0.084 mole) of2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline (preparedin Example 2) in 300 mL of methylene chloride was stirred, and 35 mL of1.0M boron tribromide in methylene chloride was added. Upon completionof addition, the reaction mixture was stirred at ambient temperature forabout 21 hours. Thin layer chromatographic analysis of the reactionmixture indicated that the reaction was not complete. The reactionmixture was heated at reflux for about 6 hours, then it was allowed tocool to ambient temperature where it was stirred for about 60 hours.After this time, the reaction mixture was poured into 500 mL of icecontaining 100 mL of concentrated ammonium hydroxide. The mixture wasfiltered to collect a solid. The solid was washed with water and driedat 70° C. under reduced pressure, yielding 2.4 grams of2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline. The NMRspectrum was consistent with the proposed structure.

Step B Synthesis of 2,4-diamino-5-chloro-6-5-chloro-2-(pyridin-2-yl-methoxy)phenyl!quinazoline (Compound 73)

Under a nitrogen atmosphere, a stirred solution of 0.5 gram (0.002 mole)of 2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline, 0.3gram (0.002 mole) of pyridin-2-ylmethyl chloride hydrochloride, and 0.5gram (0.004 mole) of potassium carbonate in 5 mL ofN,N-dimethylformamide was heated at 60° C. for about 24 hours. Afterthis time, the reaction mixture was concentrated under reduced pressureto a residue. The residue was taken up in 100 mL of water and wasstirred for about 2 hours. The resultant solid was collected byfiltration, yielding 0.6 gram of 2,4-diamino-5-chloro-6-5-chloro-2-(pyridin-2-ylmethoxy)phenyl!quinazoline. The NMR spectrum wasconsistent with the proposed structure.

Example 4

SYNTHESIS OF 2,4-DIAMINO6-BROMO-5-CHLOROQUINAZOLINE (COMPOUND 20)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 2.4 grams (0.010 mole) of2-amino-5-bromo-6-chlorobenzonitrile (prepared as in Step A of Example2) and 1.4 grams (0.012 mole) of chloroformamidine hydrochloride in 10mL of 2-methoxyethyl ether. The yield of2,4-diamino-6-bromo-5-chloroquinazoline was 2.4 grams. The NMR spectrumwas consistent with the proposed structure.

Example 5

SYNTHESIS OF 2,4-DIAMINO-5-CHLORO-6-(3,5-DICHLOROPHENYL)QUINAZOLINE(COMPOUND 51)

Step A Synthesis of 2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrileas an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 1, using 2.3 grams (0.010 mole) of2-amino-5-bromo-6-chlorobenzonitrile (prepared as in Step A of Example2), 2.9 grams (0.015 mole) of 3,5-dichlorophenylboronic acid, 0.1 gram(catalyst) of tetrakis(triphenylphosphine)palladium(0), and 30 mL ofaqueous 2M sodium carbonate in 75 mL of toluene. The solid product wasrecrystallized from toluene, yielding 1.9 grams of2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrile. The NMR spectrumwas consistent with the proposed structure.

Step B Synthesis of2,4-diamino-5-chloro-6-(3,5-dichlorophenyl)quinazoline (Compound 51)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 1.5 grams (0.005 mole) of2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrile and 0.7 gram (0.006mole) of chloroformamidine hydrochloride in 10 mL of 2-methoxyethylether. The solid was recrystallized from methanol, yielding 0.5 gram of2,4-diamino-5-chloro-6-(3,5-dichlorophenyl)quinazoline. The NMR spectrumwas consistent with the proposed structure; however, methanol waspresent in the sample.

Example 6

SYNTHESIS OF 2,4-DIAMINO-6-(2-PHENYLETHYL)QUINAZOLINE (COMPOUND 79)

Step A Synthesis of 2-amino-5-bromobenzonitrile as an intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 6.0 grams (0.051 mole) of 2-aminobenzonitrile and 9.0grams (0.051 mole) of N-bromosuccinimide in 75 mL ofN,N-dimethylformamide. The yield of 2-amino-5-bromobenzonitrile was 8.6grams. The MR spectrum was consistent with the proposed structure.

Step B Synthesis of 2-amino-5-(2-phenylethynyl)benzonitrile as anintermediate

A solution of 3.00 grams (0.015 mole) of 2-amino-5-bromobenzonitrile and2.3 mL (0.021 mole) of phenylacetylene in 50 mL of acetonitrile wasstirred, and 10.6 mL of triethylamine, 0.13 gram of copper iodide, and0.29 gram of bis(triphenylphosphine)palladium(II) chloride were added inorder. Upon completion of addition, the reaction mixture was stirred atambient temperature for about 20 hours. After this time, thin layerchromatographic (TLC) analysis of the reaction mixture indicated that noreaction had taken place. The reaction mixture was warmed to 70° C.,where it was stirred for about 7.5 hours. An additional 0.38 gram ofphenylacetylene was added, and the reaction mixture was warmed to refluxtemperature where it was stirred during about an additional 16.5 hourperiod. After this time, TLC analysis of the reaction mixture indicatedthat it contained about a 1 to 1 mixture of starting bromobenzonitrileand product. An additional 5.0 mL of triethylamine and 0.09 gram ofbis(triphenylphosphine)palladium(II) chloride catalyst was added to thereaction mixture, and the heating at reflux was continued during anadditional 24 hour period. After this time, the reaction mixture wasconcentrated under reduced pressure to a residue. The residue wasdissolved in ethyl acetate, and the solution was washed with 50 mL ofaqueous, dilute hydrochloric acid. The organic layer was dried withmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure to a residue. The residue was subjected to columnchromatography on silica gel. Elution was accomplished using 15/10/75tetrahydrofuran/methylene chloride/petroleum ether. Theproduct-containing fractions were combined and concentrated underreduced pressure, yielding 0.85 gram of2-amino-5-(2-phenylethynyl)benzonitrile. The NMR spectrum was consistentwith the proposed structure.

NOTE: The method of Taylor and Ray was used to prepare2-amino-5-(2-phenylethynyl)benzonitrile, as shown above in Step B. JOC.,52, 3997-4000 (1987)!

Step C Synthesis of 2-amino-5-(2-phenylethyl)benzonitrile as anintermediate

A solution of 0.85 gram (0.004 mole) of2-amino-5-(2-phenylethynyl)benzonitrile in 150 mL of ethanol wasprepared, and 0.2 gram (catalyst) of 10% palladium on carbon was added.The mixture was then hydrogenated using a Parr hydrogenator. Uponcompletion of the uptake of the theoretical amount of hydrogen, thereaction mixture was filtered and concentrated under reduced pressure toa residue. The residue was dried under reduced pressure, yielding 0.74gram of 2-amino-5-(2-phenylethyl)benzonitrile. The NMR spectrum wasconsistent with the proposed structure.

Step D Synthesis of 2,4-diamino-6-(2-phenylethyl)quinazoline (Compound79)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 0.74 gram (0.003 mole) of2-amino-5-(2-phenylethyl)benzonitrile and 0.41 gram (0.004 mole) ofchloroformamidine hydrochloride in 11 mL of 2-methoxyethyl ether. Theyield of 2,4-diamino-6-(2-phenylethyl)quinazoline was 0.66 gram, mp178°-180° C., sl. decomp. The NMR spectrum was consistent with theproposed structure.

Example 7

SYNTHESIS OF 2, 4-DIAMINO-6-(NAPHTH-2-YLTHIO)QUINAZOLINE (COMPOUND 88)

Step A Synthesis of 2-nitro-5-(naphth-2-ylthio)benzonitrile as anintermediate

A stirred solution of 10.0 grams (0.055 mole) of5-chloro-2-nitrobenzonitrile and 8.8 grams (0.055 mole) of2-naphthalenethiol in 80 mL of N,N-dimethylformamide was cooled to 0°C., and 7.6 grams (0.055 mole) of potassium carbonate was added. Uponcompletion of addition, the reaction mixture was stirred at 0° C. for 1hour. Thin layer chromatographic (TLC) analysis of the reaction mixtureafter this time indicated that the reaction had not gone to completion.The reaction mixture was then allowed to warm to ambient temperature,where it was stirred for about 18 hours. The reaction mixture wasstirred with 80 mL of pyridine and then was diluted with water until asolid precipitate formed. The solid was collected by filtration and waswashed in turn with an aqueous solution of 10% pyridine, water, anaqueous solution of 1 % hydrochloric acid, and finally with water. Thesolid was then dissolved in ethyl acetate and dried with magnesiumsulfate. The mixture was filtered, and the filtrate was concentratedunder reduced pressure to a residual solid. The solid was subjected tocolumn chromatography on silica gel. Elution was accomplished with 10%ethyl acetate in heptane. The product-containing fractions were combinedand concentrated under reduced pressure, yielding 13.5 grams of2-nitro-5-(naphth-2-ylthio)benzonitrile. A small sample wasrecrystallized from ethyl acetate/hexane, mp 139°-140° C. The NMRspectrum was consistent with the proposed structure.

Step B Synthesis of 2-amino-5-(naphth-2-ylthio)benzonitrile as anintermediate

A stirred solution of 13.0 grams (0.042 mole) of2-nitro-5-(naphth-2-ylthio)benzonitrile in 200 mL of 2-methoxyethylether was cooled to 0° C., and a solution of 30.3 grams (0.134 mole) ofstannous chloride dihydrate in 91 mL of concentrated hydrochloric acidwas added. Upon completion of addition, the reaction mixture was allowedto warm to ambient temperature, where it was stirred during a 2 hourperiod. After this time, the reaction mixture was poured, with stirring,into a mixture of 260 grams of aqueous 50% potassium hydroxide in 300grams of ice. An oily material, which dropped out of the solution,ultimately solidified. The solid was collected by filtration and waswashed with water. The solid was dissolved in methylene chloride and wasdried with magnesium sulfate. The mixture was filtered, and the filtratewas concentrated under reduced pressure, yielding 12.0 grams of2-amino-5-(naphth-2-ylthio)benzonitrile. The NMR spectrum was consistentwith the proposed structure.

Step C Synthesis of 2,4-diamino-6-(naphth-2-ylthio)quinazoline (Compound88)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 12.0 grams (0.043 mole) of2-amino-5-(naphth-2-ylthio)benzonitrile and 5.5 grams (0.048 mole) ofchloroformamidine hydrochloride in 25 mL of 2-methoxyethyl ether. Theyield of 2,4-diamino-6-(naphth-2-ylthio)quinazoline was 12.7 grams. TheNMR spectrum was consistent with the proposed structure.

NOTE: The compound of Example 7 was prepared by the method of Ashton andHynes. J. Med. Chem., 16, 1233-1237 (1973)!

Example 8

SYNTHESIS OF 2,4-DIAMINO-6-(NAPHTH-2-YLSULFONYL)QUINAZOLINE (COMPOUND90)

A solution of 2.0 grams (0.006 mole) of2,4-diamino-6-(naphth-2-ylthio)quinazoline (prepared in Example 7) in 80mL of acetic acid was stirred, and a solution of 2.0 grams (0.013 mole)of potassium permanganate in 75 mL of water was added dropwise during a1 hour period. Upon completion of addition, the reaction mixture wasstirred at ambient temperature for about 18 hours. After this time, thereaction mixture was filtered through diatomaceous earth. The filtratewas made basic by adding an excess amount of concentrated ammoniumhydroxide. The resultant precipitate was collected by filtration and waswashed in turn with water, methanol, and acetone. The precipitate wasstirred in hot N,N-dimethylformamide and treated with decolorizingcarbon. The mixture was filtered hot, and the filtrate was set aside.The residue collected by the filtration was again stirred with hotN,N-dimethylformamide and filtered. The two filtrates were combined andpoured into 500 grams of ice. The resultant solid was collected byfiltration, yielding 0.9 gram of2,4-diamino-6-(naphth-2-ylsulfonyl)quinazoline, mp 300°-302° C. The NMRspectrum was consistent with the proposed structure.

Example 9

SYNTHESIS OF 2,4-DIAMINO-6-(3,4-DICHLOROPHENYLTHIO)QUINAZOLINE (COMPOUND80)

Step A Synthesis of 2-nitro-5-(3,4-dichlorophenylthio)benzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step A ofExample 7, using 10.1 grams (0.006 mole) of5-chloro-2-nitrobenzonitrile, 9.9 grams (0.006 mole) of3,4-dichlorobenzenethiol, 7.7 grams (0.006 mole) of potassium carbonatein 80 mL of N,N-dimethylformamide. The yield of2-nitro-5-(3,4-dichlorophenylthio)benzonitrile was 15.9 grams, mp136°-138° C. The NMR spectrum was consistent with the proposedstructure.

Step B Synthesis of 2-amino-5-(3,4-dichlorophenylthio)benzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step B ofExample 7, using 15.9 grams (0.049 mole) of2-nitro-5-(3,4-dichlorophenylthio)benzonitrile, 34.6 grams (0.153 mole)of stannous chloride dihydrate, and 100 mL of concentrated hydrochloricacid in 245 mL of diglyme. The yield of2-amino-5-(3,4-dichlorophenylthio)benzonitrile was 15.2 grams, mp126°-128° C. The NMR spectrum was consistent with the proposedstructure.

Step C Synthesis of 2,4-diamino-6-(3,4-dichlorophenylthio)quinazoline(Compound 80)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 14.7 grams (0.050 mole) of2-amino-5-(2,4-dichlorophenylthio)benzonitrile and 6.3 grams (0.055mole) of chloroformamidine hydrochloride in 30 mL of 2-methoxyethylether. The yield of 2,4-diamino-6-(3,4-di-chlorophenylthio)quinazolinewas 12.2 grams, mp 232°-234° C. The NMR spectrum was consistent with theproposed structure.

Example 10

SYNTHESIS OF 2,4-DIAMINO-6-(3,4-DICHLOROPHENYLSULFONYL)QUINAZOLINE(COMPOUND 82)

This compound was prepared in a manner analogous to that of Example 8,using 2.0 grams (0.006 mole) of2,4-diamino-6-(3,4-dichloro-phenylthio)quinazoline and 1.9 grams (0.012mole) of potassium per-manganate in 80 mL of acetic acid and 75 mL ofwater. The yield of2,4-diamino-6-(3,4-dichlorophenylsulfonyl)quinazoline was 0.6 gram, mp286°-289° C. The NMR spectrum was consistent with the proposedstructure.

Example 11

SYNTHESIS OF 2,4-DIAMINO-5-(3,4-DICHLOROPHENYLSULFINYL)QUINAZOLINE(COMPOUND 81)

Step A Synthesis of the bromine complex of 1,4-diazabicyclo(2,2,2)-octane as an intermediate

A stirred solution of 2.2 grams (0.02 mole) of 1,4-diazabicyclo(2,2,2)octane in 10 mL of carbon tetrachloride was warmedto 40° C., and a solution of 3.2 grams (0.02 mole) of bromine in 15 mLof carbon tetrachloride was added dropwise. The resultant precipitatewas collected by filtration, washed with carbon tetrachloride, andair-dried, yielding 5.0 grams of the bromine complex of1,4-diazabicyclo(2,2,2)octane.

NOTE: The method of Oae et al. was used to prepare the bromine complexof 1,4-diazabicyclo(2,2,2)octane, as shown above in Step A. Bull. Chem.Soc. Japan, 39, 364-366 (1966)!

Step B Synthesis of2,4-diamino-6-(3,4-dichlorophenylsulfinyl)quinazoline (Compound 81)

A suspension of 5.0 grams (0.011 mole) of the bromine complex of1,4-diazabicyclo(2,2,2)octane in 200 mL of aqueous 70% acetic acid wasstirred, and 3.4 grams (0.01 mole) of2,4-diamino-6-(3,4-dichlorophenylthio)quinazoline was added portionwiseduring about a 1 hour period. Upon completion of addition, the reactionmixture was stirred at ambient temperature for about 20 hours. Afterthis time, the reaction mixture was neutralized with concentratedammonium hydroxide. The resultant solid was collected by filtration andtriturated with methanol. The solid was collected by filtration anddried, yielding 2,4-diamino-6-(3,4-dichlorophenylsulfinyl)quinazoline,mp 200° C., dec. The NMR spectrum was consistent with the proposedstructure.

Example 12

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-NITROQUINAZOLINE (COMPOUND 30)

Step A Synthesis of 2-chloro-6-methyl-5-nitrobenzonitrile as anintermediate

Under a nitrogen atmosphere, a stirred solution of aqueous 90% nitricacid was cooled to -35° C., and 40.0 grams (0.264 mole) of2-chloro-6-methylbenzonitrile was added in one portion. The reactionmixture was then allowed to warm to ambient temperature, where it wasstirred for about 18 hours. After this time, the reaction mixture waspoured into 3000 mL of ice-water. After the ice melted, the resultantsolid was collected by filtration and dried. The NMR spectrum of thesolid indicated that it was about 75% pure product. The solid wasrecrystallized twice from methanol, yielding 13.9 grams of2-chloro-6-methyl-5-nitrobenzonitrile, mp 85.5°-87.5° C. The NMRspectrum was consistent with the proposed structure. The filtrates fromthe recrystallizations were combined and concentrated under reducedpressure to a residue. The residue was subjected to columnchromatography on silica gel. Elution was accomplished using 10% ethylacetate in petroleum ether. The product-containing fractions werecombined and concentrated under reduced pressure, yielding an additional20.4 grams of 2-chloro-6-methyl-5-nitrobenzonitrile, mp 87.5°-89.5° C.The NMR spectrum was consistent with the proposed structure.

Step B Synthesis of 2,4-diamino-6-methyl-5-nitroquinazoline (Compound30)

Under a nitrogen atmosphere, a stirred solution 29.5 grams (0.150 mole)of 2-chloro-6-methyl-5-nitrobenzonitrile and 54.0 grams (0.300 mole) ofguanidine carbonate in 1500 mL of 2-ethoxyethanol was heated at refluxduring a 3.5 hour period. After this time, the reaction mixture wasconcentrated under reduced pressure to a residue. The residue wasstirred with 300 mL of water, and the resultant solid was collected byfiltration. The solid was washed with 50 mL of water and dried underreduced pressure, yielding 27.2 grams of2,4-diamino-5-methyl-6-nitroquinazoline. The NMR spectrum was consistentwith the proposed structure. The reaction was repeated again.

Example 13

SYNTHESIS OF 2,4,6-TRIAMINO-5-METHYLQUINAZOLINE (COMPOUND 32)

A mixture of 5.0 grams (0.023 mole) of2,4-diamino-5-methyl-6-nitroquinazoline (prepared in Example 12) and 0.5gram (catalyst) of 10% palladium on carbon in 200 mL of ethanol washydrogenated at 45°-50° C. using a Parr hydrogenator. The theoreticaluptake of hydrogen required about 2.5 hours. The hydrogenation wasrepeated twice more, using 15.0 grams (0.068 mole) and 11.0 grams (0.050mole), respectively, of 2,4-diamino-5-methyl-6-nitroquinazoline. Thetotal yield of 2,4,6-triamino-5-methylquinazoline was 19.5 grams. TheNMR spectra were consistent with the proposed structure.

Example 14

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-(3,4,5-TRIMETHOXYPHENYLAMINO)METHYL!QUINAZOLINE (COMPOUND 93)

Step A Synthesis of 2,4-diamino-6-cyano-5-methylquinazoline as anintermediate

Under a nitrogen atmosphere, a stirred solution of 2.5 grams (0.013mole) of 2,4,6-triamino-5-methylquinazoline (prepared in Example 13) and25 mL of 2N hydrochloric acid (0.050 mole) was cooled to 5° C., and asolution of 1.1 grams (0.016 mole) of sodium nitrite in 4 mL of waterwas added dropwise. Upon completion of addition, the reaction mixturewas stirred at 5° C. during a 10 minute period. In a separate reactionvessel, a stirred solution of 14.7 grams (0.225 mole) of potassiumcyanide in 70 mL of water was cooled to 5° C., and a solution of 1.4grams (0.056 mole) of copper(II) sulfate pentahydrate in 100 mL of waterwas added dropwise. To this solution was added, portionwise, thereaction mixture containing the quinazoline diazonium salt preparedabove. Upon completion of addition, the reaction mixture was allowed towarm to ambient temperature as it stirred during a 2 hour period. Afterthis time, the reaction mixture was diluted with 60 mL of aqueous 50%potassium carbonate and was extracted with four 700 mL portions oftetrahydrofuran. The combined extracts were acidified with 50 mL ofacetic acid, and the mixture was concentrated under reduced pressure toa residual solid. The solid was subjected twice to column chromatographyon silica gel. Elution was accomplished in each case with 20%N,N-dimethylformamide in ethyl acetate. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 1.1grams of 2,4-diamino-6-cyano-5-methylquinazoline. The NMR spectrum wasconsistent with the proposed structure; however, it showed that theproduct was in the form of the acetate salt.

Step B Synthesis of 2,4-diamino-5-methyl-6-(3,4,5-trimethoxyphenylamino)methyl!quinazoline (Compound 93)

A mixture of 1.1 grams (0.005 mole) of2,4-diamino-6-cyano-5-methylquinazoline, 4.6 grams (0.025 mole)3,4,5-trimethoxyaniline and 2.0 grams (catalyst) of Raney nickel (50%slurry in water) in 30 mL of water and 70 mL of acetic acid washydrogenated at 50 psi of hydrogen for 6 hours using a Parrhydrogenator. After this time the reaction mixture was filtered. Thefilter cake was slurried with a boiling mixture of 15 mL of water and 35mL of acetic acid and was then filtered. The filtrates were combined andsubjected to thin layer chromatography (TLC). The TLC analysis indicatedthat a small amount of the starting quinazoline remained unreacted. Thefiltrate was combined with 1.0 gram of Raney nickel and the mixture wasagain hydrogenated for an additional 1.5 hours using the Parrhydrogenator. After this time the reaction mixture was filtered andconcentrated under reduced pressure to a residual oil. The residual oilwas subjected to column chromatography on silica gel. Elution wasaccomplished initially using 25% N,N-dimethylformamide in ethyl acetateand, finally 40% N,N-dimethylformamide in ethyl acetate. Theproduct-containing fractions were combined and concentrated underreduced pressure to a residual solid. The solid was recrystallized fromwater, yielding 0.5 gram of 2,4-diamino-5-methyl-6-(3,4,5-trimethoxyphenylamino)methyl!quinazoline, mp 95°-210° C. The NMRanalysis was consistent with the proposed structure; however, itindicated that the compound was a complex with acetic acid and water.

NOTE: The compound of Example 14 is known in the literature asTrimetrexate®, for use in treatments of certain kinds of cancers. J.Med. Chem., 26, 1753-1760 (1983)!

Example 15

SYNTHESIS OF 2,4-DIAMINO-5-CHLORO-6-(3,4,5-TRIMETHOXYPHENYLMETHYL)IMINO!QUINAZOLINE COMPOUND 91

Step A Synthesis of 2,4-diamino-5-chloro-6-nitroquinazoline as anintermediate

Nitric acid (90%), 125 mL, was stirred and cooled to -10° C., and 125 mLof 98% sulfuric acid was added dropwise. Upon completion of addition,the reaction mixture temperature was brought to 0° C., and 19.7 grams(0.10 mole) of 2,4-diamino-5-chloroquinazoline (Compound 2, prepared ina manner analogous to that of Step E of Example 1) was added. Uponcompletion of addition, the reaction mixture was allowed to warm toambient temperature where it was stirred for about 18 hours. Thereaction mixture was then poured into 1500 mL of ice. The resultantmixture was made basic with 700 mL of aqueous 30% ammonia, keeping thetemperature below 30° C. The mixture was cooled in an ice-bath, and theresultant solid was collected by filtration. The solid was stirred with1000 mL of tetrahydrofuran and 500 mL of water. The mixture was filteredto remove a solid. The filtrate was diluted with 500 mL of ethyl acetateand then was concentrated under reduced pressure to a solid residue. Thetwo solids were combined, washed with ethyl acetate, and dried, yielding22.2 grams of 2,4-diamino-5-chloro-6-nitroquinazoline. The NMR spectrumwas consistent with the proposed structure.

Step B Synthesis of 2,4,6-triamino-5-chloroquinazoline (Compound 24) asan intermediate

This compound was prepared in a manner analogous to that of Example 13,using 11.0 grams (0.049 mole) of 2,4-diamino-5-chloro-6-nitroquinazolineand 1.0 gram of 10% platinum on carbon in 70 mL of 2-methoxyethanol and130 mL of ethanol, yielding 2,4,6-triamino-5-chloroquinazoline.

Step C Synthesis of 2,4-diamino-5-chloro-6-(3,4,5-trimethoxyphenylmethyl)imino!quinazoline (Compound 91)

Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.014mole) of 2,4,6-triamino-5-chloroquinazoline and 2.9 grams (0.029 mole)of 3,4,5-trimethoxybenzaldehyde in 30 mL of ethanol was heated at refluxduring a 5 hour period. After this time, the resultant slurry was mixedwith 50 mL of 2-ethoxyethanol, 70 mL of ethanol, and 2.0 grams(catalyst) of Raney nickel. The mixture was then hydrogenated at 50 psiof hydrogen during a 5 hour period using a Parr hydrogenator. Themixture was then filtered, and the filter cake was slurried with 50 mLof ethanol. The ethanol was decanted from the catalyst. The remainingsolid and catalyst were slurried with an additional 50 mL of ethanolwhich was then decanted from the catalyst. The decantates were combinedwith 100 mL of dioxane and 2.0 grams of Raney nickel and hydrogenatedduring a four hour period, as described above: The reaction mixture wasthen diluted with 200 mL of dioxane and heated to reflux, at which timecomplete solution was obtained. The solution was filtered to remove thecatalyst. The filtrate was concentrated under reduced pressure to asolid residue. The solid was recrystallized from dioxane and water,yielding 2.4 grams of solid platelets, mp 234°-235° C. The NMR spectrumindicated the solid to be 2,4-diamino-5-chloro-6-(3,4,5-trimethoxyphenylmethyl)imino!quinazoline.

Example 16

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-(3,5-DICHLOROPHENYL)QUINAZOLINE(COMPOUND 116)

Step A Synthesis of 3,5-dichlorophenylboronic acid as an intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 2, using 20.0 grams (0.073 mole) of 3,5-dichlorophenyl iodide,32.0 mL of n-butyllithium (0.080 mole-2.5M in hexanes) and 48.6 mL(0.220 mole) of triisopropyl borate. The yield of3,5-dichlorophenyl-boronic acid was 6.7 grams; mp >250° C. The NMRspectrum was consistent with the proposed structure.

Step B Synthesis of 2-amino-6-methyl-5-(3,5-dichlorophenyl)benzonitrileas an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 4.3 grams (0.024 mole) of 3,5-dichlorophenylboronicacid, 4.8 grams (0.023 mole) of 2-amino-5-bromo-6-methylbenzonitrile,about 22 mL of aqueous 2M sodium carbonate, and about 0.15 gram(catalyst) of tetrakis(triphenylphosphine)palladium(0) in 50 mL oftoluene. The yield of2-amino-6-methyl-5-(3,5-dichlorophenyl)benzonitrile was 4.4 grams, mp182° C. The NMR spectrum was consistent with the proposed structure.

Step C Synthesis of2,4-diamino-5-methyl-6-(3,5-dichlorophenyl)quinazoline (Compound 116)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 4.2 grams (0.015 mole) of2-amino-6-methyl-5-(3,5-dichlorophenyl)benzonitrile and 2.0 grams (0.017mole) of chloroformamidine hydrochloride in about 15 mL of2-methoxyethyl ether. The yield of2,4-diamino-5-methyl-6-(3,5-dichlorophenyl)quinazoline was 2.7 grams,mp >250° C. The NMR spectrum was consistent with the proposed structure.

Example 17

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-1-CHLORO-2-(4-TRIFLUOROMETHYLPHENYL)ETHENYL!QUINAZOLINE (COMPOUND 143)

Step A Synthesis of 2-amino-5-iodo-6-methylbenzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 17.5 grams (0.132 mole) of 2-amino-6-methylbenzonitrile(prepared as in Step B of Example 1) and 29.8 grams (0.132 mole) ofN-iodosuccinimide in 325 mL of N,N-dimethylformamide. The yield of2-amino-5-iodo-6-methylbenzonitrile was 28.5 grams. The NMR spectrum wasconsistent with the proposed structure.

Step B Synthesis of2-amino-5-(trimethylsilylethynyl)-6-methylbenzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step B ofExample 6, using 10.0 grams (0.039 mole) of2-amino-5-iodo-6-methylbenzonitrile, 8.3 mL (0.059 mole) of(trimethylsilyl)acetylene, 0.5 gram (catalyst) ofbis(triphenylphosphine)palladium(ll) chloride, 0.2 gram (catalyst) ofcopper(I) iodide, and 21 mL (0.156 mole) of triethylamine in 75 mL ofacetonitrile. The yield of2-amino-5-(trimethylsilylethynyl)-6-methylbenzonitrile was 6.6 grams.The NMR spectrum was consistent with the proposed structure.

Step C Synthesis of 2-amino-5-ethynyl-6-methylbenzonitrile as anintermediate

A mixture of 1.4 grams (0.006 mole) of2-amino-5-(trimethylsilylethynyl)-6-methylbenzonitrile and 0.9 gram(0.006 mole) of potassium carbonate in 50 mL of methanol was stirred atambient temperature for one hour. The reaction mixture was thenconcentrated under reduced pressure to a residue. The residue was takenup in about 75 mL of water, and the solution was extracted with two 200mL portions of diethyl ether. The combined extracts were dried withmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure, yielding 1.0 gram of2-amino-5-ethynyl-6-methylbenzonitrile. The NMR spectrum was consistentwith the proposed structure. This reaction was repeated several times.

Step D Synthesis of 2-amino-6-methyl-5-(4-trifluoromethylphenyl)ethynyl!benzonitrile as an intermediate

A solution of 3.5 grams (0.022 mole) of2-amino-5-ethynyl-6-methylbenzonitrile, 8.4 grams (0.031 mole) of4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) oftriethylamine, 0.5 gram (catalyst) ofbis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst)of copper(l) iodide in 100 mL of acetonitrile was stirred at ambienttemperature for about 18 hours. After this time the reaction mixture wasconcentrated under reduced pressure to a residue. The residue waspartitioned between ethyl acetate and aqueous 1N hydrochloric acid. Thetwo-layered mixture was filtered to remove a solid. The aqueous layerand the organic layer were separated, and the aqueous layer was washedwith ethyl acetate. The ethyl acetate wash was combined with the organiclayer, and the combination was washed with an aqueous solution of 10%lithium chloride. The organic layer was dried with magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure to aresidue. The residue was triturated with methylene chloride andfiltered. The filtrate was subjected to column chromatography on silicagel. Elution was accomplished using methylene chloride. Theproduct-containing fractions were combined and concentrated underreduced pressure, yielding 4.8 grams of 2-amino-6-methyl-5-(4-trifluoromethylphenyl)ethynyl!benzonitrile, mp 136°-138° C. The NMRspectrum was consistent with the proposed structure.

Step E Synthesis of 2,4-diamino-5-methyl-6-1-chloro-2-(4-trifluoromethylphenyl)ethenyl!quinazoline (Compound 143)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 2.7 grams (0.009 mole) of 2-amino-6-methyl-5-(4-trifluoromethylphenyl)ethynyl!benzonitrile and 1.2 grams (0.011 mole)of chloroformamidine hydrochloride in 10 mL of 2-methoxyethyl ether.Upon completion of the reaction, the reaction mixture was diluted with200 mL of diethyl ether. The resultant solid was collected byfiltration, and was dissolved in a hot mixture of 300 mL of water and100 mL of n-propanol. The solution was filtered hot through a sinteredglass funnel to remove some insoluble material. The filtrate was thenmade basic with 100 mL of concentrated ammonium hydroxide. The resultantsolid was collected by filtration, and dried at 60° C. under vacuum. Thesolid was then dissolved in a solution of 10% methanol in methylenechloride, and the solution was subjected to column chromatography onsilica gel. Elution was accomplished using 10% methanol in methylenechloride. The product-containing fractions were combined andconcentrated under reduced pressure, yielding 1.6 grams of2,4-diamino-5-methyl-6-1-chloro-2-(4-trifluoromethylphenyl)ethenyl!quinazoline, mp >300° C. TheNMR spectrum was consistent with the proposed structure.

Example 18

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-(5-CHLOROTHIEN-2-YL)QUINAZOLINE(COMPOUND 146)

Step A Synthesis of (5-chlorothien-2-yl)tributyl tin as an intermediate

A stirred solution of 5.1 mL (0.046 mole) of 2-bromo-5-chlorothiophenein 200 mL of tetrahydrofuran was cooled to -85°C., and 19.7 mL (0.049mole) of n-butyllithium (0.049 mole-2.5M in hexanes) was added dropwiseduring a 15 minute period. The reaction mixture temperature wasmaintained at -85° C. to -80° C. throughout the addition. Uponcompletion of addition, the reaction mixture temperature was maintainedat about -80° C. for one hour. After this time, a solution of 12.5 mL(0.046 mole) of tributyltin chloride in 50 mL of tetrahydrofuran wasadded to the cold reaction mixture during a 10 minute period. Uponcompletion of addition, the reaction mixture was stirred at -80° C. forone hour, then it was allowed to warm gradually to ambient temperature.The reaction was quenched with an aqueous solution saturated withammonium chloride, and then the reaction mixture was extracted withthree 150 mL portions of diethyl ether. The combined extracts were driedwith magnesium sulfate and filtered. The filtrate was concentrated underreduced pressure, yielding 18.4 grams of (5-chlorothien-2-yl)tributyltin. The NMR spectrum was consistent with the proposed structure.

Step B Synthesis of 2-amino-6-methyl-5-(5-chlorothien-2-yl)benzonitrileas an intermediate

A solution of 5.9 grams (0.015 mole) of (5-chlorothien-2-yl)tributyl tinand 3.0 grams (0.015 mole) of 2-amino-5-iodo-6-methylbenzonitrile in 150mL of toluene was stirred, and 0.2 gram (catalyst) oftetrakis(triphenylphosphine)palladium(0) was added. The reaction vesselwas evacuated, and then back-filled with dry nitrogen gas. This processwas repeated two more times. The reaction mixture was then heated toreflux where it was stirred for about 18 hours. After this time thereaction mixture was concentrated under reduced pressure to a residue.The residue was dissolved in methylene chloride, and the solution wasfiltered through a fiber-glass pad to remove the catalyst. The filtratewas subjected to column chromatography on silica gel. Elution wasaccomplished using methylene chloride. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 2.0grams of 2-amino-6-methyl-5-(5-chlorothien-2-yl)benzonitrile, mp108°-110° C. The NMR spectrum was consistent with the proposedstructure.

Step C Synthesis of2,4-diamino-5-methyl-6-(5-chlorothien-2-yl)quinazoline (Compound 146)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 1.6 grams (0.007 mole) of2-amino-6-methyl-5-(5-chlorothien-2-yl)benzonitrile and 0.8 gram (0.008mole) of chloroformamidine hydrochloride in 10 mL of 2-methoxyethylether. The yield of2,4-diamino-5-methyl-6-(5-chlorothien-2-yl)quinazoline was 1.1 grams, mp270°-272° C., dec. The NMR spectrum was consistent with the proposedstructure.

Example 19

SYNTHESIS OF2,4-DIAMINO-5-METHYL-6-(4-TRIFLUOROMETHYLPHENYLCARBONYL)QUINAZOLINE(COMPOUND 158)

Step A Synthesis of2-amino-5-(4-trifluoromethylphenylcarbonyl)-6-methylbenzonitrile as anintermediate

A mixture of 2.6 grams (0.01 mole) of2-amino-5-iodo-6-methylbenzonitrile (prepared in Step A of Example 17),8.3 grams (0.0125 mole) of tetramethylammoniumtetra(4-trifluoromethylphenyl)borate, and 0.1 gram (0.0005 mole) ofpalladium(II) acetate in 50 mL of N,N-dimethylformamide is placed in ahigh pressure reaction vessel. The stirring reaction mixture is thenplaced under 1 atmosphere of carbon monoxide gas, where it is maintainedat about 60° C. for a 30 hour period. After this time, the cooledreaction mixture is removed from the reaction vessel and is filtered toremove catalyst and salts. The filtrate is concentrated under reducedpressure to a residue. The residue is partitioned between methylenechloride and water. The methylene chloride-product solution is thensubjected to column chromatography on silica gel. Elution isaccomplished with methylene chloride. The product-containing fractionsare combined and concentrated under reduced pressure, yielding about 2.0grams of2-amino-5-(4-trifluoromethylphenylcarbonyl)-6-methylbenzonitrile.

Step B Synthesis of2,4-diamino-5-methyl-6-(4-trifluorophenylcarbonyl)quinazoline (Compound158)

This compound is prepared in a manner analogous to that of Step E ofExample 1, using 2.0 grams (0.009 mole) of2-amino-5-(4-trifluoromethylphenylcarbonyl)-6-methylbenzonitrile and 0.9gram (0.009 mole) chloroformamidine hydrochloride in 20 mL of2-methoxyethyl ether, yielding2,4-diamino-5-methyl-6-(4-trifluorophenylcarbonyl)quinazoline.

Example 20

SYNTHESIS OF2,4-DIAMINO-5-METHYL-6-(3-FLUORO-5-TRIFLUOROMETHYLPHENYL)QUINAZOLINE(COMPOUND 188)

Step A Synthesis of 3-fluoro-5-trifluoromethylphenylboronic acid as anintermediate

A crystal of iodine and 0.5 gram (0.021 mole) of magnesium turnings wereplaced in a reaction vessel containing 10 mL of tetrahydrofuran. To thiswas added dropwise 2 mL of a solution of 5.0 grams (0.021 mole) of3-fluoro-5-trifluoromethylphenyl bromide in 65 mL of tetrahydrofuran.The Grignard formation was initiated by warming the reaction vessel toabout 45° C. The remaining 3-fluoro-5-trifluoromethylphenylbromide--tetrahydrofuran solution was added portionwise at a rate whichmaintained gentle reflux of the reaction mixture.

In a second reaction vessel, 40 mL of tetrahydrofuran was cooled to -78°C., and 2.3 mL (0.021 mole) of trimethyl borate was added dropwise asthe Grignard reagent of 3-fluoro-5-trifluoromethylphenyl bromideprepared above was transferred into the second reaction vessel using acannula. The temperature of the reaction mixture was maintained below-60° C. during the additions. Upon completion of the additions, thereaction mixture was again cooled to -78° C., where it was stirred forabout 45 minutes. After this time, the reaction mixture was allowed towarm to ambient temperature. The reaction mixture was then poured intoabout 200 mL of water and was made acidic with aqueous 5% hydrochloricacid. The mixture was extracted with four 100 mL portions of ethylacetate. The combined extracts were dried with magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure, yielding3.3 grams of 3-fluoro-5-trifluoromethylphenylboronic acid, mp 167°-168°C. The NMR spectrum was consistent with the proposed structure.

Step B Synthesis of2-amino-6-methyl-5-(3-fluoro-5-trifluoromethylphenyl)benzonitrile as anintermediate

Under a dry nitrogen atmosphere, 0.5 gram (0.0004 mole) oftetrakis(triphenylphosphine)palladium(0) was added to a stirred mixtureof 2.8 grams (0.0132 mole) of 2-amino-5-bromo-6-methylbenzonitrile(prepared as in Step C of Example 1), 35 mL of aqueous 2M sodiumcarbonate and 50 mL of toluene. To this was then added dropwise asolution of 3.3 grams (0.0159 mole) of3-fluoro-5-trifluoromethylphenylboronic acid in 10 mL of ethanol. Uponcompletion of addition, the reaction mixture was warmed to about 80° C.,where it was stirred for seven hours. After this time the reactionmixture was poured into 200 mL of water. The mixture was then extractedwith four 100 mL portions of ethyl acetate. The combined extracts weredried with magnesium sulfate and filtered. The filtrate was concentratedunder reduced pressure to a residue. The residue was subjected to columnchromatography on silica gel. Elution was accomplished with methylenechloride. The product-containing fractions were combined andconcentrated under reduced pressure, yielding 4.0 grams of2-amino-6-methyl-5-(3-fluoro-5-trifluoromethylphenyl)benzonitrile, mp96°-97° C. The NMR spectrum was consistent with the proposed structure.

Step C Synthesis of2,4-diamino-5-methyl-6-(3-fluoro-5-trifluoromethylphenyl)quinazoline(Compound 188)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 3.7 grams (0.013 mole) of2-amino-6-methyl-5-(3-fluoro-5-trifluoromethylphenylbenzonitrile and 1.7grams (0.015 mole) of chloroformamidine hydrochloride in 25 mL of2-methoxyethyl ether. The yield of2,4-diamino-5-methyl-6-(3-fluoro-5-trifluoromethylphenyl)quinazoline was2.8 grams, mp 225°-226° C. The NMR spectrum was consistent with theproposed structure.

Example 21

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-3-(4-FLUOROPHENYL)PHENYL!QUINAZOLINE (COMPOUND 196)

Step A Synthesis of 3-(4-fluorophenyl)phenyl bromide as an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 6.2 grams (0.044 mole) of 4-fluorophenylboronic acid(commercially available), 25.0 grams (0.100 mole) of 1,3-dibromobenzene,0.2 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), 75 mLof aqueous 2M sodium carbonate, and 75 mL of toluene. The yield of3-(4-fluorophenyl)phenyl bromide was 7.1 grams. The NMR spectrum wasconsistent with the proposed structure.

Step B Synthesis of 3-(4-fluorophenyl)phenylboronic acid as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 2, using 7.1 grams (0.028 mole) of 3-(4-fluorophenyl)phenylbromide, 17 mL (0.034 mole) of n-butyllithium (2.0M in hexanes), and 9.5mL (0.084 mole) of trimethyl borate in 100 mL of tetrahydrofuran. Theyield of 3-(4-fluorophenyl)phenylboronic acid was about 3.5 grams. TheNMR spectrum was consistent with the proposed structure.

Step C Synthesis of 2-amino-6-methyl-5-3-(4-fluorophenyl)phenyl!benzonitrile as an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 3.4 grams (0.016 mole) of3-(4-fluorophenyl)phenylboronic acid, 3.3 grams (0.016 mole) of2-amino-5-bromo-6-methylbenzonitrile, 0.2 gram (catalyst) oftetrakis(triphenylphosphine)palladium(0), 50 mL of aqueous 2M sodiumcarbonate, and 50 mL of toluene. The yield of 2-amino-6-methyl-5-3-(4-fluorophenyl)phenyl!benzonitrile was 4.8 grams. The NMR spectrumwas consistent with the proposed structure.

Step D Synthesis of 2,4-diamino-5-methyl-6-3-(4-fluorophenyl)phenyl!-quinazoline (Compound 196)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 2.0 grams (0.007 mole) of 2-amino-6-methyl-5-3-(4-fluorophenyl)phenyl!benzonitrile and 0.8 gram (0.007 mole) ofchloroformamidine hydrochloride in 10 mL of 2-methoxyethyl ether. Theyield of 2,4-diamino-5-methyl-6- 3-(4-fluorophenyl)phenyl!quinazolinewas 0.5 gram. The NMR spectrum was consistent with the proposedstructure.

Example 22

SYNTHESIS OF 2,4-DIAMINO-5-METHYL-6-3-(4-CHLOROPHENOXY)PHENYL!QUINAZOLINE (COMPOUND 205)

Step A Synthesis of 3-(4-chlorophenoxy)phenyl bromide as an intermediate

Under a nitrogen atmosphere, a solution of 13.6 grams (0.106 mole) of4-chlorophenol in 50 mL of diglyme was stirred, and 24.1 mL (0.106 mole)of methanolic 25% sodium methoxide was added dropwise. Upon completionof addition, the reaction mixture was heated to about 165° C. to removemethanol. After the methanol was removed, the heating was ceased, and25.0 grams (0.106 mole) of 1,3-dibromobenzene and 1.3 grams of cuprousbromide were added. Upon completion of the additions, the reactionmixture was heated to reflux where it was stirred for about 21 hours.The reaction mixture was then cooled and filtered. The filter cake waswashed with diethyl ether, and the wash was combined with the filtrate.The combination was extracted with two 20 mL portions of aqueous 20%sodium hydroxide and then with two 75 mL portions of an aqueous solutionsaturated with sodium chloride. The organic layer was dried withmagnesium sulfate and filtered.

The filtrate was concentrated under reduced pressure to a residual oil.The oil was distilled under vacuum, yielding about 9.0 grams of3-(4-chlorophenoxy)phenyl bromide, bp 110° C./0.5 mm Hg. The NMRspectrum was consistent with the proposed structure.

Step B Synthesis of 3-(4-chlorophenoxy)phenylboronic acid as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 2, using 9.0 grams (0.032 mole) of 3-(4-chlorophenoxy)phenylbromide, 14 mL (0.035 mole) of n-butyllithium (2.5M in hexanes), and10.4 mL (0.095 mole) of trimethyl borate in 100 mL of tetrahydrofuran.The yield of 3-(4-chlorophenoxy)phenylboronic acid was about 7.6 grams.The NMR spectrum was consistent with the proposed structure.

Step D Synthesis of 2-amino-6-methyl-5-3-(4-chlorophenoxyphenyl!-benzonitrile as an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 7.6 grams (0.031 mole) of3-(4-chlorophenoxy)phenylboronic acid, 6.5 grams (0.031 mole) of2-amino-5-bromo-6-methylbenzonitrile, about 0.2 gram (catalyst) oftetrakis(triphenylphosphine)palladium(0), about 30 mL of aqueous 2Msodium carbonate, and about 50 mL of toluene. The yield of2-amino-6-methyl-5- 3-(4-chlorophenoxy)phenyl!-benzonitrile was 2.0grams. The NMR spectrum was consistent with the proposed structure.

Step E Synthesis of 2,4-diamino-5-methyl-6-3-(4-chlorophenoxy)phenyl!-quinazoline (Compound 205)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 1.8 grams (0.005 mole) of 2-amino-6-methyl-5-3-(4-chlorophenoxy)phenyl!benzonitrile and 0.6 gram (0.005 mole) ofchloroformamidine hydrochloride in about 10 mL of 2-methoxyethyl ether.The yield of 2,4-diamino-5-methyl-6-3-(4-chlorophenoxy)phenyl!quinazoline was 0.9 gram. The NMR spectrum wasconsistent with the proposed structure.

Example 23

SYNTHESIS OF2,4-DIAMINO-5-METHYL-6-(6-CHLORO-2,3-DIHYDRO-2,2-DIMETHYLBENZOFURAN-4-YL)QUINAZOLINE(COMPOUND 210)

Step A Synthesis of 2-methyl-3-(3-chloro-2-cyanophenoxy)-1-propene as anintermediate

A solution of 30.0 grams (0.174 mole) of 2,6-dichlorobenzonitrile and14.7 mL (0.174 mole) of 2-methyl-2-propen-1-ol in 200 mL of dimethylsulfoxide was stirred, and 12.7 grams (0.191 mole) of 85% potassiumhydroxide was added portionwise during a 5 minute period. During theaddition, the reaction mixture temperature rose from 20° C. to about 35°C. Upon completion of the addition, the reaction mixture was stirred atambient temperature for about 18 hours. After this time the reactionmixture was poured into 600 mL of water. The mixture was filtered tocollect a solid. The solid was washed with water and dried under vacuum,yielding 33.9 grams of 2-methyl-3-(3-chloro-2-cyanophenoxy)-1-propene.The NMR spectrum was consistent with the proposed structure.

Step B Synthesis of 6-chloro-7-cyano-2,3-dihydro-2,2-dimethylbenzofuranas an intermediate

A stirred mixture of 33.9 grams (0.163 mole) of2-methyl-3-(3-chloro-2-cyanophenoxy)-1-propene and 0.2 gram (0.0017mole) of magnesium chloride was warmed to 180° C. during a one hourperiod, where it was stirred for about six hours. The product, whichsublimed to the top of the reaction vessel, was subjected to columnchromatography on silica gel. Elution was accomplished using 1:1methylene chloride and petroleum ether. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 25.8grams of 6-chloro-7-cyano-2,3-dihydro-2,2-dimethylbenzofuran. The NMRspectrum was consistent with the proposed structure.

Step C Synthesis of7-aminocarbonyl-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran as anintermediate

A stirred solution of 10.0 grams (0.048 mole) of6-chloro-7-cyano-2,3-dihydro-2,2-dimethylbenzofuran in 200 mL of2-methyl-2-propanol was warmed to reflux, and 9.5 grams (0.17 mole) of85% potassium hydroxide was added in one portion. Upon completion ofaddition, the reaction mixture was heated at reflux for about 75minutes. The reaction mixture was then cooled and poured into 400 mL ofwater that was cooled in an ice bath. The resultant solid was collectedby filtration and dried under vacuum, yielding 8.2 grams of7-aminocarbonyl-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMRspectrum was consistent with the proposed structure.

Step D Synthesis of 7-amino-6-chloro-2,3-dihydro-2,2-dimethylbenzofuranas an intermediate

A stirred solution of 5.8 grams (0.145 mole) of sodium hydroxide in 100mL of water was cooled to 0° C., and 7.3 grams (0.045 mole) of brominewas added dropwise during a 5 minute period. Upon completion ofaddition, the mixture was stirred for 5 minutes, and an emulsion of 8.2grams (0.036 mole) of7-aminocarbonyl-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran in 75 mL ofdioxane was added portionwise during a 15 minute period. Upon completionof addition, the reaction mixture was stirred at 0° C. for one hour. Thereaction mixture was warmed to 75° C. during a two hour period, where itwas stirred for 19 hours. After this time the reaction mixture wascooled and poured into 300 mL of water. The mixture was then extractedwith two 200 mL portions of ethyl acetate. The combined extracts werewashed with an aqueous solution saturated with sodium chloride and driedwith magnesium sulfate. The mixture was filtered and concentrated underreduced pressure to a residue. The residue was subjected to columnchromatography on silica gel. Elution was accomplished using methylenechloride. The product containing fractions were combined andconcentrated under reduced pressure, yielding 4.5 grams of7-amino-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrumwas consistent with the proposed structure.

Step E Synthesis of7-amino-4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 4.5 grams (0.023 mole) of7-amino-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran and 4.1 grams (0.023mole) of N-bromosuccinimide in 50 mL of N,N-dimethylformamide. The yieldof 7-amino-4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran was 5.1grams. The NMR spectrum was consistent with the proposed structure.

Step F Synthesis of 4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuranas an intermediate

A stirred solution of 5.1 grams (0.018 mole) of7-amino-4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran and 25 mL oftoluene in 100 mL of ethanol was cooled in an ice bath, and 2 mL (0.036mole) of concentrated sulfuric acid was added slowly. Upon completion ofaddition, 2.0 grams (0.029 mole) of sodium nitrite was then added. Theice bath was then removed, and the reaction mixture was warmed to 75°C., where it stirred for minutes. After this time the reaction mixturewas warmed to 95° C., where it stirred for one hour. The reactionmixture was then cooled and poured into 200 mL of water. The mixture wasextracted with two 150 mL portions of diethyl ether. The combinedextracts were dried with magnesium sulfate and filtered. The filtratewas concentrated under reduced pressure to a residue. The residue wassubjected to column chromatography on silica gel. Elution wasaccomplished using petroleum ether. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 3.6grams of 4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMRspectrum was consistent with the proposed structure.

Step G Synthesis of6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-ylboronic acid as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 2, using 3.6 grams (0.014 mole) of4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran, 5.5 mL (0.014 mole)of n-butyllithium (2.5M in hexanes), and 4.7 mL (0.042 mole) oftrimethyl borate in 75 mL of 15 tetrahydrofuran. The yield of6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-ylboronic acid was 3.0grams. The NMR spectrum was consistent with the proposed structure.

Step H Synthesis of2-amino-6-methyl-5-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)benzonitrileas an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 3.0 grams (0.013 mole) of6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl-boronic acid, 2.1 grams(0.031 mole) of 2-amino-5-iodo-6-methylbenzonitrile (prepared as in StepA of Example 17), 0.12 gram (catalyst) oftetrakis(triphenylphosphine)palladium(0), 10 mL of aqueous 2M sodiumcarbonate, and 100 mL of toluene. The yield of2-amino-6-methyl-5-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)benzonitrilewas 1.9 grams. The NMR spectrum was consistent with the proposedstructure.

Step I Synthesis of2,4-diamino-5-methyl-6-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)quinazoline(Compound 210)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 1.7 grams (0.005 mole) of2-amino-6-methyl-5-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)benzonitrileand 0.8 gram (0.006 mole) of chloroformamidine hydrochloride in 15 mL of2-methoxyethyl ether. The yield of2,4-diamino-5-methyl-6-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)quinazolinewas 1.2 grams. The NMR spectrum was consistent with the proposedstructure.

Example 24

SYNTHESIS OF 2,4-DIAMINO-7-FLUORO-5-METHYL-6-3,5-DI(TRIFLUOROMETHYL)PHENYL!QUINAZOLINE (COMPOUND 214)

Step A Synthesis of 5-fluoro-2-methylcarbonylamino-3-methylnitrobenzeneas an intermediate

Stirred acetic anhydride, 300 mL, was cooled to about 70° C., and 25.1grams (0.20 mole) of 4-fluoro-2-methylaniline was added dropwise duringa 30 minute period. Upon completion of addition, the reaction mixturewas stirred at about 10° C. for an additional 15 minutes. In a separatereaction vessel, acetyl nitrate was prepared by the dropwise addition of14.9 mL of 90% nitric acid to 30 mL of stirred, cold (0°-15° C.) aceticanhydride during a 15 minute period. The so-prepared acetyl nitrate wascooled to about -5° C., placed in a dropping funnel, and added dropwiseduring a 30 minute period to the 2-methylaniline solution. Uponcompletion of addition, the reaction mixture was stirred an additional 5hours. After this time the reaction mixture was poured into 400 grams ofice. The resultant solid was collected by filtration, washed with water,and dried at 60° C. under vacuum, yielding 23.0 grams of5-fluoro-2-methylcarbonylamino-3-methylnitrobenzene, mp 167°-172° C. TheNMR spectrum was consistent with the proposed structure.

Step B Synthesis of 4-fluoro-2-nitro-6-methylaniline as an intermediate

A stirred solution of 22.4 grams (0.106 mole) of5-fluoro-2-methylcarbonylamino-3-methyinitrobenzene, 100 mL ofconcentrated hydrochloric acid, and 100 mL of ethanol was heated atreflux for about 17 hours. The reaction mixture was cooled and pouredinto 500 grams of ice. The mixture was made basic with aqueous 50%sodium hydroxide. The resultant solid was collected by filtration andwas thoroughly washed with water. The solid was dried at about 60° C.under vacuum, yielding 17.0 grams of 4-fluoro-2-nitro-6-methylaniline,mp 111°-113°C. The NMR spectrum was consistent with the proposedstructure. The reaction was repeated to obtain more product.

Step C Synthesis of 4-fluoro-2-nitro-6-methylphenyl iodide as anintermediate

A mixture of 4.4 grams (0.026 mole) of 4-fluoro-2-nitro-6-methylaniline,13.2 grams (0.052 mole) of iodine, and 5.5 grams (0.029 mole) ofcopper(I) iodide in 125 mL of acetonitrile was stirred, and a solutionof 4.6 mL (0.039 mole) of tert-butyl nitrite in 25 mL of acetonitrilewas added dropwise during a 10 minute period. Upon completion ofaddition, the reaction mixture was stirred at ambient temperature forabout 16 hours. After this time the reaction mixture was poured into 300mL of water. Excess iodine was destroyed using sodium meta-bisulfite.The mixture was then extracted with two 250 mL portions of diethylether. The combined extracts were dried with magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure to aresidue. The residue was subjected to column chromatography on silicagel. Elution was accomplished using 1:3 methylene chloride:petroleumether. The product-containing fractions were combined and concentratedunder reduced pressure, yielding 3.4 grams of4-fluoro-2-nitro-6-methylphenyl iodide. The NMR spectrum was consistentwith the proposed structure. The reaction was repeated to obtain moreproduct.

Step D Synthesis of 4-fluoro-2-nitro-6-methylbenzonitrile as anintermediate

A stirred mixture of 19.0 grams (0.068 mole) of4-fluoro-2-nitro-6-methylphenyl iodide and 7.0 grams (0.078 mole) ofcopper(I) cyanide in 100 mL of N,N-dimethylformamide was heated at150°-155° C. for 30 minutes. The reaction mixture was then diluted with400 mL of water and 100 mL of ethyl acetate. The mixture was filtered,and the filtrate was placed in a separatory funnel. The organic layerwas separated, and the aqueous layer was washed with 200 mL of ethylacetate. The combined wash and organic layer was then washed with three150 mL portions of aqueous 5% lithium chloride. The mixture was driedwith magnesium sulfate and filtered. The filtrate was concentrated underreduced pressure to a residue. The residue was subjected to columnchromatography on silica gel. Elution was accomplished using 1:1methylene chloride: petroleum ether. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 12.8grams of 4-fluoro-2-nitro-6-methylbenzonitrile, mp 61°-63° C. The NMRspectrum was consistent with the proposed structure. Step E Synthesis of2-amino-4-fluoro-6-methylbenzonitrile as an intermediate

This compound was prepared in a manner analogous to that of Step B ofExample 1, using 12.5 grams (0.069 mole) of4-fluoro-2-nitro-6-methylbenzonitrile, 25.4 mL (0.251 mole) ofcyclohexene, 1.9 grams (catalyst) of 10% palladium on charcoal, and 10mL of water in 200 mL of ethanol. The yield of2-amino-4-fluoro-6-methylbenzonitrile was 2.0 grams. The NMR spectrumwas consistent with the proposed structure.

Step F Synthesis of 2-amino-5-bromo-4-fluoro-6-methylbenzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 0.5 gram (0.003 mole) of2-amino-4-fluoro-6-methylbenzonitrile and 0.6 gram (0.004 mole) ofN-bromosuccinimide in 30 mL of N,N-dimethylformamide. The yield of2-amino-5-bromo-4-fluoro-6-methylbenzonitrile was 0.7 gram. The NMRspectrum was consistent with the proposed structure.

Step G Synthesis of 2-amino-4-fluoro-6-methyl-5-3,5-di(trifluoromethyl)phenyl!benzonitrile as an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 1.3 grams (0.005 mole) of3,5-di(trifluoromethyl)phenylboronic acid, (commercially available) 0.7gram (0.003 mole) of 2-amino-5-bromo-4-fluoro-6-methylbenzonitrile , 0.2gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), 4.7 mL(0.009 mole) of aqueous 2M sodium carbonate, and 50 mL of toluene. Theyield of 2-amino-4-fluoro-6-methyl-5-3,5-di(trifluoromethyl)phenyl!benzonitrile was 0.9 gram. The NMRspectrum was consistent with the proposed structure.

Step H Synthesis of 2,4-diamino-7-fluoro-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline (Compound 214)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 0.9 gram (0.002 mole) of 2-amino-4-fluoro-6-methyl-5-3,5-di(trifluoromethyl)phenyl!benzonitrile and 0.3 gram (0.003 mole) ofchloroformamidine hydrochloride in 6 mL of 2-methoxyethyl ether. Theyield of 2,4-diamino-7-fluoro-5-methyl-6- 3,5-di(trifluoromethyl)phenyl!quinazoline was 0.4 grams, mp 224°-225° C. TheNMR spectrum was consistent with the proposed structure.

Example 25

SYNTHESIS OF 2,4-DI (1,1-DIMETHYLETHOXY)CARBONYLAMINO!-5-METHYL-6-3,5-DI(TRIFLUOROMETHYL)PHENYL!QUINAZOLINE (COMPOUND 217)

A stirred mixture of 2.00 grams (0.0050 mole) of 2,4-diamino-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline (Compound 63), 0.06 gram(0.0005 mole) of dimethylaminopyridine, and 10.00 grams (0.0458 mole) ofdi-tert-butyl dicarbonate was heated at 75° C. for about 6 hours. Thereaction mixture was cooled and dissolved in ethyl acetate. The solutionwas passed through a column of silica gel. Elution was accomplishedusing ethyl acetate. The eluate was concentrated under reduced pressureto a residue. The residue was triturated with hexane to remove unreacteddi-tert-butyl dicarbonate. The yield of 2,4-di(1,1-dimethylethoxy)carbonylamino!-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline was 1.2 grams. The NMRspectrum was consistent with the proposed structure.

Example 26

SYNTHESIS OF 2,4-DIAMINO-5-(1-METHYLETHYL)-6- 3,5-35DI(TRIFLUOROMETHYL)PHENYL!QUINAZOLINE (COMPOUND 219)

Step A Synthesis of 2-methylcarbonylamino-3-(1-methylethyl)-nitrobenzeneas an intermediate

This compound was prepared in a manner analogous to that of Step A ofExample 24, using 19.1 grams (0.141 mole) of 2-(1-methylethyl)anilineand 7.9 mL (0.169 mole) of 90% nitric acid in about 85 mL of aceticanhydride. The yield of2-methylcarbonylamino-3-(1-methylethyl)nitrobenzene was 30.0 grams. TheNMR spectrum was consistent with the proposed structure.

Step B Synthesis of 2-nitro-6-(1-methylethyl)aniline as an intermediate

This compound was prepared in a manner analogous to that of Step B ofExample 24, using 30.0 grams (0.135 mole) of2-methylcarbonylamino-3-(1-methylethyl)nitrobenzene, 50 mL ofconcentrated hydrochloric acid, and 50 mL of ethanol. The yield of2-nitro-6-(1-methylethyl)aniline was 12.8 grams. The NMR spectrum wasconsistent with the proposed structure.

Step C Synthesis of 2-nitro-6-(1-methylethyl)phenyl iodide as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 24, using 10.7 grams (0.059 mole)2-nitro-6-(1-methylethyl)aniline, 10.5 mL (0.089 mole) of tert-butylnitrite, and 15.0 grams (0.059 mole) of iodine in 250 mL ofacetonitrile. The yield of 2-nitro-6-(1-methylethyl)phenyl iodide was15.2 grams. The NMR spectrum was consistent with the proposed structure.

Step D Synthesis of 2-nitro-6-(1-methylethyl)benzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step D ofExample 24, using 15.0 grams (0.052 mole) of2-nitro-6-(1-methylethyl)phenyl iodide and 5.4 mL (0.060 mole) ofcopper(l) cyanide in 75 mL of N,N-dimethylformamide. The yield of2-nitro-6-(1-methylethyl)benzonitrile was 9.3 grams. The NMR spectrumwas consistent with the proposed structure.

Step E Synthesis of 2-amino-6-(1-methylethyl)benzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step B ofExample 1, using 9.3 grams (0.049 mole) of2-nitro-6-(1-methylethyl)benzonitrile 18.0 mL (0.178 mole) ofcyclohexene, 2.0 grams (catalyst) of 10% palladium on charcoal, and 10mL of water in 250 mL of ethanol. The yield of2-amino-6-(1-methylethyl)benzonitrile was 7.4 grams. The NMR spectrumwas consistent with the proposed structure.

Step F Synthesis of 2-amino-5-bromo-6-(1-methylethyl)benzonitrile as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 7.0 grams (0.044 mole) of2-amino-6-(1-methylethyl)benzonitrile and 7.8 grams (0.044 mole) ofN-bromosuccinimide in 150 mL of N,N-dimethylformamide. The yield of2-amino-5-bromo-6-(1-methylethyl)benzonitrile was 8.4 grams, mp 82°-85°C. The NMR spectrum was consistent with the proposed structure.

Step G Synthesis of 2-amino-6-(1-methylethyl)-5-3,5-di(trifluoromethyl)phenyl!benzonitrile as an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 3.1 grams (0.011 mole) of3,5-di(trifluoromethyl)phenylboronic acid, 1.8 grams (0.008 mole) of2-amino-5-bromo-6-(1-methylethyl)benzonitrile, 0.3 gram (catalyst) oftetrakis(triphenyl-phosphine)palladium(0), 12.0 mL (0.024 mole) ofaqueous 2M sodium carbonate, and 200 mL of toluene. The yield of2-amino-6-(1-methylethyl)-5- 3,5-di-(trifluoromethyl)phenyl!benzonitrilewas 2.2 grams. The NMR spectrum was consistent with the proposedstructure.

Step H Synthesis of 2,4-diamino-5-(1-methylethyl)-6-3,5-di(trifluoromethyl)phenyl!quinazoline (Compound 219)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 1.9 grams (0.005 mole) of 2-amino-6-(1-methylethyl)-5-3,5-di(trifluoromethyl)phenyl!benzonitrile and 0.7 gram (0.006 mole) ofchloroformamidine hydrochloride in 25 mL of 2-methoxyethyl ether. Theyield of 2,4-diamino-5-(1-methylethyl)-6-3,5-di(trifluoromethyl)phenyl!quinazoline was 0.4 grams, mp 212°-214° C.The NMR spectrum was consistent with the proposed structure.

Example 27

SYNTHESIS OF2,4-DIAMINO-5-METHYL-6-(2,3-DIHYDRO-2,2-DIMETHYL-3-BENZOFURANON-4-YL)QUINAZOLINE(COMPOUND 212)

Step A Synthesis of 7-amino-4-bromo-2,3-dihydro-2,2-dimethylbenzofuranas an intermediate

A stirred solution of 10.0 grams (0.061 mole) of7-amino-2,3-dihydro-2,2-dimethylbenzofuran in 150 mL ofN,N-dimethylformamide was cooled in an ice-water bath, and asolution of10.9 grams (0.061 mole) of N-bromosuccinimide in 50 mL ofN,N-dimethylformamide was added in one portion. Upon completion ofaddition, the reaction mixture was maintained in the ice-water bath forabout one hour. After this time the reaction mixture was poured intoabout 600 mL of water. The mixture was then extracted with two 200 mLportions of diethyl ether. The combined extracts were washed with two100 mL portions of an aqueous 10% lithium chloride solution. The organiclayer was dried with magnesium sulfate and filtered. The filtrate wasconcentrated under reduced pressure, yielding 12.3 grams of7-amino-4-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum wasconsistent with the proposed structure.

Step B Synthesis of 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran as anintermediate

A stirred solution of 12.3 grams (0.051 mole) of7-amino-4-bromo-2,3-dihydro-2,2-dimethylbenzofuran and 30 mL of toluenein 200 mL of ethanol was cooled in an ice-bath, and 5.6 mL (0.102 mole)of concentrated sulfuric acid was added slowly, followed by 5.6 grams(0.082 mole) of sodium nitrite. Upon completion of addition, theice-bath was removed, and the reaction mixture was warmed to 50° C. Thereaction mixture temperature was then brought to about 75° C., where itwas stirred for 30 minutes. After this time the reaction mixture washeated at reflux for one hour and then was poured into 200 mL of water.The mixture was extracted with two 150 mL portions of diethyl ether. Thecombined extracts were dried with magnesium sulfate and filtered. Thefiltrate was concentrated under reduced pressure to a residual oil. Theoil was subjected to column chromatography on silica gel. Elution wasaccomplished using petroleum ether. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 3.6grams of 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrumwas consistent with the proposed structure.

Step C Synthesis of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone asan intermediate

Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.013mole) 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran, 10.7 grams (0.039mole) of potassium persulfate, and 3.3 grams (0.013 mole) of copper(II)sulfate pentahydrate in 30 mL of water and 30 mL of acetonitrile washeated at reflux for one hour. After this time the reaction mixture waspoured into 200 mL of water. The mixture was then extracted with one 200mL portion of diethyl ether. The extract was dried with magnesiumsulfate and filtered. The filtrate was concentrated under reducedpressure to a residual oil. The oil was subjected to columnchromatography on silica gel. Elution was accomplished using 1:1petroleum ether and methylene chloride. The product-containing fractionswere combined and concentrated under reduced pressure, yielding 2.1grams of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone. The NMRspectrum was consistent with the proposed structure. Steps A through Cwere repeated.

Step D Synthesis of 2,4-diamino-5-methylquinazoline (compound 27) as anintermediate

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 1 0.0 grams (0.076 mole) of2-amino-6-methylbenzonitrile (prepared as in Example 1, Step B), and10.0 grams (0.087 mole) of chloroformamidine hydrochloride in 40 mL of2-methoxyethyl ether, yielding 11.5 grams of2,4-diamino-5-methylquinazoline. The NMR spectrum was consistent withthe proposed structure.

Step E Synthesis of 2,4-diamino-6-acetoxymercurio-5-methylquinazoline asan intermediate

A solution of 10.0 grams (0.057 mole) of 2,4-diamino-5-methylquinazolineand 18.2 grams (0.057 mole) of mercuric acetate in 125 mL of acetic acidis stirred at ambient temperature for about 18 hours. After this timethe reaction mixture is poured into 1000 mL of water. The resultantprecipitate is collected by filtration and dried, yielding2,4-diamino-6-acetoxymercurio-5-methylquinazoline.

Step F Synthesis of (2,4-diamino-5-methylquinazolin-6-yl)boronic acid asan intermediate

A solution of 17.3 grams (0.040 mole) of2,4-diamino-6-acetoxymercurio-5-methylquinazoline and 38.3 mL (0.400mole) of boranetetrahydrofuran complex (1.0M in tetrahydrofuran). in1000 mL of tetrahydrofuran is stirred at ambient temperature for about30 minutes. The reaction mixture is then poured into water. Theresultant precipitate is collected by filtration and dried, yielding(2,4-diamino-5-methylquinazolin-6-yl)boronic acid.

NOTE: The method of S.W. Breuer and F.G. Thorpe (Tetrahedron Lett.No.42, pp 3719-3720, 1974) is used to prepare2,4-diamino-5-methylquinazolin-6-yl)boronic acid from its6-acetoxymercurio derivative.

Step G Synthesis of2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)quinazoline(Compound 212)

A solution of 2.1 grams (0.010 mole) of(2,4-diamino-5-methylquinazolin-6-yl)boronic acid in 25 mL ofN,N-dimethylformamide is stirred, and 2.1 grams (0.009 mole) of4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone (prepared in Step C ofthis Example), 2.8 grams (0.020 mole) of potassium carbonate, and 0.31gram (catalyst-3 mole %) of tetrakis(triphenylphosphine)palladium(0) areadded. The reaction mixture is then warmed to 90° C., where it isstirred for about 16 hours. After this time the reaction mixture ispoured into water. The resultant precipitate is collected by filtrationand dried, yielding2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)quinazoline.

NOTE: The methods of A. Suzuki et al. (J. Am. Chem. Soc. 1989, 111,314-321) and W. C. Shieh et al. (J. Org. Chem. 1992, 57, 379-381) areused to prepare2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)quinazoline.

Example 28

SYNTHESIS OF 2,4-DI(DIMETHYLAMINOMETHYLENEAMINO)-5-

METHYL-6- 3,5-DI(TRIFLUOROMETHYL)PHENYL!QUINAZOLINE (COMPOUND 272)

Under a nitrogen atmosphere, a stirred solution of 1.0 gram (0.0026mole) of 2,4-diamino-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline (Compound 63-prepared as inExample 1) in 20 mL of dimethylformamide dimethyl acetal was heated at80° C. for about 18 hours. After this time, the reaction mixture wascooled and concentrated under reduced pressure to a residue. The residuewas then triturated with petroleum ether, and the resulting solid wascollected by filtration. The filter cake was washed with petroleum etherand dried, yielding about 1.1. grams of2,4-di(dimethylaminomethyleneamino)-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline, mp 208°-210° C. The NMRspectrum was consistent with the proposed structure.

Example 29

SYNTHESIS OF 2,4-DIAMINO-6-(4--CHLOROPHENOXY)QUINAZOLINE (COMPOUND 242)

Step A Synthesis of 2-nitro-5-(4-chlorophenoxy)benzonitrile as anintermediate

Sodium hydride (60% in mineral oil), 1.5 grams (0.038 mole) was washedin petroleum ether. The petroleum ether was decanted , and the sodiumhydride was suspended in about 20 mL of N,N-dimethylformamide. Thesuspension was stirred, and solutions of 4.5 grams (0.035 mole) of4-chlorophenol in 20 mL of N,N-dimethylformamide and 5.0 grams (0.027mole) of 5-chloro-2-nitrobenzonitrile in 20 mL of N,N-dimethylformamidewere added, respectively. Upon completion of addition, the reactionmixture was warmed to reflux where it stirred for about 18 hours. Thereaction mixture was then cooled and poured into a mixture of 500 mL ofwater and 50 mL of aqueous 2N sodium hydroxide. The mixture was stirredfor about 15 minutes, then it was allowed to stand for about 18 hours.The resultant solid was collected by filtration and recrystallized fromethanol, yielding 3.9 grams of 2-nitro-5-(4-chlorophenoxy)benzonitrile,mp 120°-122° C. The NMR spectrum was consistent with the proposedstructure.

Step B Synthesis of 2-amino-5-(4-chlorophenoxy)benzonitrile as anintermediate

A mixture of 2.0 grams (0.035 mole) of iron powder, 1.0 mL ofconcentrated hydrochloric acid, 4.0 mL of water, in 30 mL of ethanol wasstirred, and 2.5 grams (0.009 mole) of2-nitro-5-(4-chlorophenoxy)benzonitrile was added slowly. Uponcompletion of addition, the reacton mixture was warmed to reflux whereit stirred for about seven hours. After this time, the reaction mixturewas allowed to cool to ambient temperature where it stirred for about 18hours. The reaction mixture was then warmed and filtered through a padof diatomaceous earth. The filtrate was concentrated under reducedpressure to a residue. The residue was purified with columnchromatography on silica gel, using 1:1 petroleum ether/methylenechloride. The product-containing fractions were combined andconcentrated under reduced pressure, yielding 0.2 gram of2-amino-5-(4-chlorophenoxy)benzonitrile, mp 116°-118° C. The NMRspectrum was consistent with the proposed structure. The reaction wasrepeated.

Step C Synthesis of 2,4-diamino-6-(4-chlorophenoxy)quinazoline (Compound242)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 0.5 gram (0.002 mole) of2-amino-5-(4-chlorophenoxy)benzonitrile and 0.3 gram (0.003 mole) ofchloroformamidine hydrochloride in 5 mL of 2-methoxyethyl ether. Theyield of 2,4-diamino-6-(4-chlorophenoxy)quinazoline was 0.5 gram, mp226°-228° C. The NMR spectrum was consistent with the proposedstructure.

Example 30

SYNTHESIS OF2,4-DIAMINO-6-(2,3-DIHYDRO-2,2,6-TRIMETHYLBENZOFURAN-4-YL)-5-METHYLQUINAZOLINE(COMPOUND 225)

Step A Synthesis of 2-methyl-3-(3-methyl-2-nitrophenoxy)-1-propene as anintermediate

A mixture of 20.0 grams (0.130 mole) of 3-methyl-2-nitrophenol and 22.5grams (0.163 mole) of potassium carbonate in 200 mL of dimethylsulfoxide was stirred, and 15.3 mL (0.156 mole) of methallyl chloridewas added dropwise during a five minute period. Upon completion ofaddition, 5.4 grams (0.033 mole) of potassium iodide was added in oneportion. The reaction mixture was then stirred at ambient temperaturefor about 18 hours. After this time the reaction mixture was poured into500 mL of water. The mixture was then extracted with two 200 mL portionsof diethyl ether. The combined extracts were dried with magnesiumsulfate and filtered. The filtrate was concentrated under reducedpressure, yielding 27.0 grams of2-methyl-3-(3-methyl-2-nitrophenoxy)-1-propene. The NMR spectrum wasconsistent with the proposed structure.

Step B Synthesis of 2,3-dihydro-2,2,6-trimethyl-7-nitrobenzofuran as anintermediate

A stirred mixture of 26.5 grams (0.128 mole) of2-methyl-3-(3-methyl-2-nitrophenoxy)-1-propene and 0.4 gram (0.004 mole)of magnesium chloride was warmed to 180° C. during one hour, where itwas maintained for four additional hours. The reaction mixture wascooled, yielding 26.5 grams of2,3-dihydro-2,2,6-trimethyl-7-nitrobenzofuran. The NMR spectrum wasconsistent with the proposed structure.

Step C Synthesis of 7-amino-2,3-dihydro-2,2,6-trimethylbenzofuran as anintermediate

This compound was prepared in a manner analogous to that of Step C ofExample 6, using 21.8 grams (0.1 05 mole) of2,3-dihydro-2,2,6-trimethyl-7-nitrobenzofuran, hydrogen gas, and 0.2gram (catalyst) of platinum oxide in 50 mL of ethanol. The yield of7-amino-2,3-dihydro-2,2,6-trimethylbenzofuran was 14.5 grams.

Step D Synthesis of7-amino-4-bromo-2,3-dihydro-2,2,6-trimethylbenzofuran as an intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 14.1 grams (0.080 mole) of7-amino-2,3-dihydro-2,2,6-trimethylbenzofuran and 14.2 grams (0.080mole) of N-bromosuccinimide in 250 mL of N,N-dimethylformamide. Theyield of 7-amino-4-bromo-2,3-dihydro-2,2,6-trimethylbenzofuran was 17.7grams. The NMR spectrum was consistent with the proposed structure.

Step E Synthesis of 4-bromo-2,3-dihydro-2,2,6-trimethylbenzofuran as anintermediate

This compound was prepared in a manner analogous to that of Step F ofExample 23, using 17.2 grams (0.067 mole) of7-amino-4-bromo-2,3-dihydro-2,2,6-trimethylbenzofuran, 7.4 grams (0.107mole) of sodium nitrite, and 7.5 mL (0.134 mole) of concentratedsulfuric acid in 75 mL of toluene and 300 mL of ethanol. The yield of4-bromo-2,3-dihydro-2,2,6-trimethylbenzofuran was 10.4 grams. The NMRspectrum was consistent with the proposed structure.

Step F Synthesis of 2,3-dihydro-2,2,6-trimethylbenzofuran-4-ylboronicacid as an intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 2, using 10.1 grams (0.042 mole) of4-bromo-2,3-dihydro-2,2,6-trimethylbenzofuran, 16.8 mL (0.042 mole) ofn-butyllithium (2.5M in hexanes), and 14.3 mL (0.126 mole) of trimethylborate in 100 mL of tetrahydrofuran. The yield of2,3-dihydro-2,2,6-trimethylbenzofuran-4-ylboronic acid was 8.3 grams.The NMR spectrum was consistent with the proposed structure.

Step G Synthesis of2-amino-5-(2,3-dihydro-2,2,6-trimethylbenzofuran-4-yl)-6-methylbenzonitrileas an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 8.0 grams (0.039 mole) of2,3-dihydro-2,2,6-trimethylbenzofuran-4-ylboronic acid, 6.7 grams (0.026mole) of 2-amino-5-iodo-6-methylbenzonitrile (prepared as in Step A ofExample 17), 0.2 gram (catalyst) oftetrakis(triphenylphosphine)palladium(0), 33 mL of aqueous 2M sodiumcarbonate, and 200 mL of toluene. The yield of2-amino-5-(2,3-dihydro-2,2,6-trimethylbenzofuran-4-yl)-6-methylbenzonitrilewas 7.5 grams. The NMR spectrum was consistent with the proposedstructure.

Step H Synthesis of2,4-diamino-6-(2,3-dihydro-2,2,6-trimethylbenzofuran-4-yl)-5-methylquinazoline(Compound 225)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 7.1 grams (0.024 mole) of2-amino-5-(2,3-dihydro-2,2,6-trimethylbenzofuran-4-yl)-6-methylbenzonitrileand 3.4 grams (0.029 mole) of chloroformamidine hydrochloride in 15 mLof 2-methoxyethyl ether. The yield of2,4-diamino-6-(2,3-dihydro-2,2,6-trimethylbenzofuran-4-yl)-5-methylquinazolinewas 5.4 grams. The NMR spectrum was consistent with the proposedstructure.

Example 31

SYNTHESIS OF2,4-DIAMINO-6-(2,3-DIHYDRO-2,2-DIMETHYL-6-TRIFLUOROMETHYLBENZOFURAN4-YL)-5-METHYLQUINAZOLINE (COMPOUND 226)

Step A Synthesis of2-methyl-3-(2-cyano-3-trifluoromethylphenoxy)-1-propene as anintermediate

This compound was prepared in a manner analogous to that of Step A ofExample 23, using 25.0 grams (0.132 mole) of2-fluoro-6-trifluoromethylbenzonitrile, 12.3 mL (0.135 mole) of2-methyl-2-propen-1-ol, and 10.0 grams (0.135 mole) of powdered 85%potassium hydroxide in 250 mL of dimethyl sulfoxide. The yield of2-methyl-3-(2-cyano-3-trifluoromethylphenoxy)-1-propene was 28.6 grams.The NMR spectrum was consistent with the proposed structure.

Step B Synthesis of7-cyano-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran as anintermediate

This compound was prepared in a manner analogous to that of Step B ofExample 30, using 28.1 grams (0.116 mole) of2-methyl-3-(2-cyano-3-trifluoromethylphenoxy)-1-propene and 0.3 gram(0.003 mole) of magnesium chloride. The yield of7-cyano-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran was 27.5grams, mp 79°-83° C. The NMR spectrum was consistent with the proposedstructure.

Step C Synthesis of7-aminocarbonyl-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran asan intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 23, using 27.0 grams (0.112 mole) of7-cyano-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran and 12.6grams (0.224 mole) of powdered 85% potassium hydroxide in 250 mL of2-methyl-2-propanol. The yield of7-aminocarbonyl-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran was13.0 grams. The NMR spectrum was consistent with the proposed structure.

Step D Synthesis of7-amino-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran as anintermediate

This compound was prepared in a manner analogous to that of Step D ofExample 23, using 12.6 grams (0.049 mole) of7-aminocarbonyl-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran,7.8 grams (0.196 mole) of sodium hydroxide, 3.8 grams (0.074 mole) ofbromine in 150 mL of water and 150 mL of dioxane. The yield of7-amino-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran was 7.5grams. The NMR spectrum was consistent with the proposed structure. StepE Synthesis of7-amino-4-bromo-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran asan intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 1, using 7.2 grams (0.031 mole) of7-amino-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran and 5.5grams (0.031 mole) of N-bromosuccinimide in about 100 mL ofN,N-dimethylformamide. The yield of7-amino-4-bromo-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran was9.5 grams. The NMR spectrum was consistent with the proposed structure.

Step F Synthesis of4-bromo-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran as anintermediate

This compound was prepared in a manner analogous to that of Step F ofExample 23, using 9.3 grams (0.030 mole) of7-amino-4-bromo-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran.3.3 grams (0.048 mole) of sodium nitrite, and 3.3 mL (0.060 mole) ofconcentrated sulfuric acid in 50 mL of toluene and 150 mL of ethanol.The yield of4-bromo-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran was 7.7grams. The NMR spectrum was consistent with the proposed structure.

Step G Synthesis of2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-ylboronic acid asan intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 2, using 7.4 grams (0.025 mole) of4-bromo-2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran, 10.0 mL(0.025 mole) of n-butyllithium (2.5M in hexanes), and 18.5 mL (0.108mole) of trimethyl borate in 75 mL of tetrahydrofuran. The yield of2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-ylboronic acidwas 6.4 grams. The NMR spectrum was consistent with the proposedstructure.

Step H Synthesis of2-amino-5-(2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-yl)-6-methylbenzonitrileas an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 6.4 grams (0.024 mole) of2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-ylboronic acid,3.1 grams (0.024 mole) of 2-amino-5-iodo-6-methylbenzonitrile (preparedas in Step A of Example 17), 0.2 gram (catalyst) oftetrakis(triphenylphosphine)palladium(0), 15 mL of 2M sodium carbonate,and 75 mL of toluene. The yield of2-amino-5-(2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-yl)-6-methylbenzonitrilewas 3.7 grams. The NMR spectrum was consistent with the proposedstructure.

Step I Synthesis of2,4-diamino-6-(2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-yl)-5-methylquinazoline(Compound 226)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 3.3.grams (0.009 mole) of2-amino-5-(2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-yl)-6-methylbenzonitrileand 1.3 grams (0.011 mole) of chloroformamidine hydrochloride in 20 mLof 2-methoxyethyl ether. The yield of2,4-diamino-6-(2,3-dihydro-2,2-dimethyl-6-trifluoromethylbenzofuran-4-yl)-5-methylquinazolinewas 2.7 grams. The NMR spectrum was consistent with the proposedstructure.

Example 32

SYNTHESIS OF 2,4-DI(1-OXO-3,6,9-TRIOXADECANEAMINO)-5-METHYL-6-3,5-DI(TRIFLUOROMETHYL)PHENYL!QUINAZOLINE (COMPOUND 267)

Step A Synthesis of 3,6,9-trioxadecanoyl chloride as an intermediate

Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams(0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45minute period. Upon completion of addition, the reaction mixture waswarmed to reflux where it stirred for 45 minutes. The reaction mixturewas cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acidchloride was assumed.

Step B Synthesis of 3,6,9-trioxadecanoic anhydride as an intermediateThe cooled reaction mixture from Step A was stirred, diluted with 50 mLof toluene, and 7.1 grams (0.090 mole) of pyridine was added. To thiswas added dropwise 8.0 grams (0.045 mole) of 3,6,9-trioxadecanoic acid.Upon completion of addition, the reaction mixture was stirred at ambienttemperature for one hour. The reaction mixture was then filtered toremove a precipitate. The filtrate was concentrated under reducedpressure, yielding 14.0 grams of 3,6,9-trioxadecanoic anhydride. The NMRspectrum was consistent with the proposed structure.

Step C Synthesis of 2,4-di(1-oxo-3,6,9-trioxadecaneamino)-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline (Compound 267)

Under a nitrogen atmosphere, a stirred solution of 1.5 grams (0.004mole) of 2,4-diamino-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline (Compound 63-prepared as inExample 1), 3.9 grams (0.012 mole) of 3,6,9-trioxadecanoic anhydride,1.2 grams (0.016 mole) of pyridine, and 0.14 gram (0.001 mole) ofdimethylaminopyridine in 20 mL of dioxane was heated at reflux for sevenhours. After this time, the reaction mixture was poured into 400 mL ofice-water. The mixture was stirred until the ice melted, and then it wasfiltered to collect a gummy solid. The solid was dissolved in diethylether and washed in turn with two 25 mL portions of aqueous 10% citricacid, 25 mL of an aqueous solution saturated with sodium chloride, 25 mLof an aqueous solution saturated with sodium bicarbonate, and 25 mL ofan aqueous solution saturated with sodium chloride. The organic layerwas dried with sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure, yielding about 0.8 gram of2,4-di(1-oxo-3,6,9-trioxadecaneamino)-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline. The NMR spectrum wasconsistent with the-proposed structure.

Example 33

SYNTHESIS OF2,4-DIAMINO-6-(6--CHLORO-2,2-DIMETHYLBENZODIOXOL-4-YL)-5-METHYLQUINAZOLINE(COMPOUND 235)

Step A Synthesis of 2-bromo-4-chlorocatechol as an intermediate

A stirred solution of 25.0 grams (0.106 mole) of2-bromo-4-chloro-5-formylphenol in 106 mL (0.106 mole) of aqueous 1Nsodium hydroxide was warmed to about 50° C., and 150 mL (0.133 mole) ofaqueous 3% hydrogen peroxide was added dropwise. Upon completion ofaddition, the reaction mixture was allowed to cool to ambienttemperature as it stirred for about 18 hours. After this time, thereaction mixture was made acidic with aqueous 6N hydrochloric acid. Themixture was then filtered to collect a solid. The solid was washed withwater and dried under vacuum, yielding 21.2 grams of2-bromo-4-chlorocatechol. The NMR spectrum was consistent with theproposed structure.

Step B Synthesis of 4-bromo-6-chloro-2,2-dimethylbenzodioxole as anintermediate

A solution of 4.7 grams (0.021 mole) of 2-bromo-4-chlorocatechol and 10mL (0.136 mole) of acetone in 100 mL of methylene chloride was stirred,and 18.0 grams (0.128 mole) of phosphorus pentoxide was added in oneportion. Upon completion of addition, the reaction mixture was stirredat ambient temperature for about 18 hours. After this time, thesupernatant liquid was decanted from a solid residue. The residue waswashed with methylene chloride, and the wash was combined with thesupernatant liquid. The combination was then washed twice each withaqueous 1N sodium hydroxide and an aqueous solution saturated withsodium chloride. The organic layer was dried with magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure to aresidue. The residue was subjected to column chromatography on silicagel, using 5% ethyl acetate in pentane as the eluant. Theproduct-containing fractions were combined and concentrated underreduced pressure, yielding about 0.9 gram of4-bromo-6-chloro-2,2-dimethylbenzodioxole. The NMR spectrum wasconsistent with the proposed structure. The reaction was repeated.

Step C Synthesis of 6-chloro-2,2-dimethylbenzodioxol-4-ylboronic acid asan intermediate

This compound was prepared in a manner analogous to that of Step C ofExample 2, using 5.8 grams (0.022 mole) of4-bromo-6-chloro-2,2-dimethylbenzodioxole, 0.5 gram (0.022 mole) ofmagnesium turnings, and 3.4 grams (0.033 mole) of trimethyl borate in100 mL of tetrahydrofuran. The yield of6-chloro-2,2-dimethylbenzodioxol-4-ylboronic acid was about four grams.The NMR spectrum was consistent with the proposed structure.

Step D Synthesis of2-amino-5-(6-chloro-2,2-dimethylbenzodioxol-4-yl)-6-methylbenzonitrileas an intermediate

This compound was prepared in a manner analogous to that of Step D ofExample 2, using 1.9 grams (0.009 mole) of2-amino-5-bromo-6-methylbenzonitrile, 4.0 grams (0.018 mole) of6-chloro-2,2-dimethylbenzodioxol-4-ylboronic acid, 15 mL (0.009 mole) ofaqueous 2N sodium carbonate, and 0.1 gramoftetrakis(triphenylphosphine)palladium(0) in 10 mL of toluene. Theyield of2-amino-5-(6-chloro-2,2-dimethylbenzodioxol-4-yl)-6-methylbenzonitrilewas 2.1 grams, mp 156°-161° C. The NMR spectrum was consistent with theproposed structure. tep E Synthesis of2,4-diamino-6-(6-chloro-2,2-dimethylbenzodioxol-4-yl)-5-methylquinazoline(Compound 235)

This compound was prepared in a manner analogous to that of Step E ofExample 1, using 1.8 grams (0.006 mole) of2-amino-5-(6-chloro-2,2-dimethylbenzodioxol-4-yl)-6-methylbenzonitrileand 0.8 gram (0.008 mole) of chloroformamidine hydrochloride in 10 mL of2-methoxyethyl ether. The yield of2,4-diamino-6-(6-chloro-2,2-dimethylbenzodioxol-4-yl)-5-methylquinazolinewas 0.9 gram, mp 235°-238° C. The NMR spectrum was consistent with theproposed structure.

                                      TABLE 1    __________________________________________________________________________    Substituted 2,4-Diaminoquinazolines as Insecticides    __________________________________________________________________________     ##STR48##    Where R.sup.1, R.sup.2, R.sup.6 and R.sup.7 are hydrogen.    Cmpd. No.             W            X             Y    Z    __________________________________________________________________________     1       H            H             H    H     2       Cl           H             H    H     3       F            H             H    H     4       Br           H             H    H     5       I            H             H    H     6       H            Cl            H    H     7       H            Cl            H    H                          NH.sub.4.sup.+ Cl.sup.-                          complex     8       H            Br            H    H     9       H            F             H    H    10       H            H             Cl   H    11       H            H             Br   H    12       H            H             F    H    13       H            H             I    H    14       H            H             H    F    15       H            Cl            H    Cl    16       H            Br            H    Br    17       F            F             H    H    18       H            F             F    H    19       H            H             F    F    20       Cl           Br            H    H    21       H            Cl            H    Br    22       H            Br            H    Cl    23       Cl           CN            H    H    24       Cl           NH.sub.2      H    H    25       Cl           Br            H    Br    26       F            F             F    F    27       CH.sub.3     H             H    H    28       H            CH.sub.3      H    H    29       H            H             CH.sub.3                                             H    30       CH.sub.3     NO.sub.2      H    H    31       CH.sub.3     H             H    NO.sub.2    32       CH.sub.3     NH.sub.2      H    H    33       CF.sub.3     H             H    H    34       H            CF.sub.3      H    H    35       H            H             H    CF.sub.3    36       OC.sub.2 H.sub.5                          H             H    H    37       OCH.sub.2 CF.sub.3                          H             H    H    38       H            NH.sub.2      H    H    39       N(CH.sub.3).sub.2                          H             H    H    40       CN           H             H    H    41       phenyl       H             H    H    42       H            phenyl        H    H    43       H            H             phenyl                                             H    44       H                           ##STR49##    H    H    45       H                           ##STR50##    H    H    46       H            (footnote 1)  H    H    47       Cl           phenyl        H    H    48       Cl                           ##STR51##    H    H    49       Cl                           ##STR52##    H    H    50       Cl                           ##STR53##    H    H    51       Cl Methanol Solvate                           ##STR54##    H    H    52       Cl                           ##STR55##    H    H    53       Cl                           ##STR56##    H    H    54       Cl                           ##STR57##    H    H    55       H            Cl            H    phenyl    56       H            phenyl        H    Cl    57       phenyl       H             phenyl                                             H    58       H            phenyl        H    phenyl                          monohydrate    59       Cl           phenyl        H    phenyl    60       CH.sub.3                           ##STR58##    H    H    61       CH.sub.3  Methanol Solvate                           ##STR59##    H    H    62       CH.sub.3                           ##STR60##    H    H    63       CH.sub.3                           ##STR61##    H    H    64              ##STR62##                           ##STR63##    H    H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen; W is    chloro; and X is     ##STR64##    Cmpd. No.             R.sup.3    __________________________________________________________________________    65                    H    66                    CH.sub.3    67                    C.sub.5 H.sub.11    68                    C.sub.11 H.sub.23    69                    CH.sub.2 Si(CH.sub.3).sub.3    70                           ##STR65##    71                           ##STR66##    72                           ##STR67##    73                           ##STR68##    74                           ##STR69##    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6 and R.sup.7 are hydrogen.    Cmpd. No.           W                 X               Y  Z    __________________________________________________________________________    75            ##STR70##        H               H  H    76            ##STR71##        H               H  H    77            ##STR72##        H               H  H    78            ##STR73##        H               H  H    79     H                              ##STR74##      H  H    80     H                              ##STR75##      H  H    81     H                              ##STR76##      H  H    82     H                              ##STR77##      H  H    83            ##STR78##        H               H  H    84            ##STR79##        H               H  H    85            ##STR80##        H               H  H    86            ##STR81##        H               H  H    87            ##STR82##        H               H  H    88     H                              ##STR83##      H  H    89     H                              ##STR84##      H  H    90     H                              ##STR85##      H  H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y, and Z are hydrogen; and X    is     ##STR86##    Cmpd. No.  W     Q.sup.(2) n        m    R.sup.4    __________________________________________________________________________     91        Cl    NCH       1        0    H     92        Cl    CH.sub.2 NH                               1        0    H                               Hemimethanol     93        CH.sub.3                     CH.sub.2 NH                               1        0    H     94        H     CH.sub.2 NH                               1        1    H                               2.HCl     95        H     CH.sub.2 NH                               1        1    C.sub.2 H.sub.5     96        H     CH.sub.2 NH                               2        1    H                               2.HCl     97        H     CH.sub.2 NH                               2        1    C.sub.2 H.sub.5     98        H     CH.sub.2 NH                               3        1    H                               2.HCl     99        H     CH.sub.2 NH                               3        1    C.sub.2 H.sub.5    100        Cl    CH.sub.2 NH                               2        1    C.sub.2 H.sub.5    101        CH.sub.3                     CH.sub.2 NH                               2        1    H                               2.HCl    102        CH.sub.3                     CH.sub.2 NH                               2        1    C.sub.2 H.sub.5    __________________________________________________________________________     ##STR87##    Where R.sup.1, R.sup.2, R.sup.6 and R.sup.7 are hydrogen.    Cmpd. No        W       X       Y       Z    __________________________________________________________________________    103             F       H       F       H    104             F       H       H       Cl    105             H       Cl      H       F    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y, and Z are hydrogen.    Cmpd. No.        W        X    __________________________________________________________________________    106              H                               ##STR88##    107              H                               ##STR89##    108              H                               ##STR90##    109              H                               ##STR91##    110              H                               ##STR92##    111              H                               ##STR93##    112              CH.sub.3 phenyl    113              CH.sub.3                               ##STR94##    114              CH.sub.3                               ##STR95##    115              CH.sub.3                               ##STR96##    116              CH.sub.3                               ##STR97##    117              CH.sub.3                               ##STR98##    118              CH.sub.3                               ##STR99##    119              CH.sub.3                               ##STR100##    120              CH.sub.3                               ##STR101##    121              CH.sub.3                               ##STR102##    122              CH.sub.3                               ##STR103##    123              CH.sub.3                               ##STR104##    124              CH.sub.3                               ##STR105##    125              CH.sub.3                               ##STR106##    126              CH.sub.3                               ##STR107##    127              CH.sub.3                               ##STR108##    128              CH.sub.3                               ##STR109##    129              CH.sub.3                               ##STR110##    130              CH.sub.3                               ##STR111##    131              CH.sub.3                               ##STR112##    132              CH.sub.3                               ##STR113##    133              CH.sub.3                               ##STR114##    134              CH.sub.3                               ##STR115##    135              CH.sub.3                               ##STR116##    136              CH.sub.3                               ##STR117##    137              CH.sub.3                               ##STR118##    138              CH.sub.3                               ##STR119##    139              CH.sub.3                               ##STR120##    140              CH.sub.3                               ##STR121##    141              CH.sub.3                               ##STR122##    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen; W is    methyl; and X is     ##STR123##    Cmpd. No    V.sup.1                      W.sup.1 X.sup.1 Y.sup.1 Z.sup.1    __________________________________________________________________________    142         H     H       H       H       H    143         H     H       CF.sub.3                                      H       H    144         H     CF.sub.3                              H       CF.sub.3                                              H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen.           Cmpd. No   W          X    __________________________________________________________________________           145        CH.sub.3                                  ##STR124##           146        CH.sub.3                                  ##STR125##           147        CH.sub.3                                  ##STR126##           148        CF.sub.3                                  ##STR127##    __________________________________________________________________________     ##STR128##    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y, and Z are hydrogen; W is    methyl; and X is:     ##STR129##    Cmpd. No.             V.sup.2                  W.sup.2     X.sup.2     Y.sup.2                                               Z.sup.2    __________________________________________________________________________    149      H    H           H           H    H    150      Cl   H           H           H    H    151      H    Cl          H           H    H    152      H    Cl          H           Cl   H    153      H    Cl          Cl          H    H    154      H    H           Cl          H    H    155      CF.sub.3                  H           H           H    H    156      H    CF.sub.3    H           H    H    157      H    CF.sub.3    H           CF.sub.3                                               H    158      H    H           CF.sub.3    H    H    159      H    CO.sub.2 CH.sub.3                              H           H    H    160      F    H           H           H    H    161      H    H           CO.sub.2 CH.sub.3                                          H    H    162      H    F           H           H    H    163      H    CN          H           H    H    164      H    F           H           F    H    165      H    H           CN          H    H    166      H    H           F           H    H    167      F    H           F           H    F    168      H                   ##STR130## H           H    H    169      H                   ##STR131## H           H    H    170      H                   ##STR132## H           H    H    171      H    H                               ##STR133## H    H    172      H    H                               ##STR134## H    H    173      H    H                               ##STR135## H    H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y, and Z are hydrogen; and X    is:     ##STR136##    Cmpd. No.   W.sup.3                      V.sup.3                            W.sup.3                                  X.sup.3                                        Y.sup.3                                             Z.sup.3    __________________________________________________________________________    174         H     H     H     Cl    Cl   H    175         Cl    H     H     Cl    Cl   H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen; W is    methyl; and X is:             Cmpd. No.      X    __________________________________________________________________________             176                             ##STR137##             177                             ##STR138##             178                             ##STR139##             179                             ##STR140##             180                             ##STR141##             181                             ##STR142##    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen; W is    methyl; and X is:     ##STR143##    Cmpd. No      V.sup.1                        W.sup.1 X.sup.1                                      Y.sup.1                                            Z.sup.1    __________________________________________________________________________    182           H     CF3     H     H     H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen; W is    methyl; and X is:            Cmpd. No.    X    __________________________________________________________________________            183                          ##STR144##            184                          ##STR145##            185                          ##STR146##            186                          ##STR147##            187                          ##STR148##            188                          ##STR149##            189                          ##STR150##            190                          ##STR151##            191                          ##STR152##            192                          ##STR153##            193                          ##STR154##            194                          ##STR155##            195                          ##STR156##            196                          ##STR157##            197                          ##STR158##            198                          ##STR159##            199                          ##STR160##            200                          ##STR161##            201                          ##STR162##            202                          ##STR163##            203                          ##STR164##            204                          ##STR165##            205                          ##STR166##            206                          ##STR167##            207                          ##STR168##    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7 and Z are hydrogen, W is methyl,    and X is:     ##STR169##    Cmpd. No.      A         B        D     E    __________________________________________________________________________    208            O         CH.sub.2 H     H    209            CH.sub.2  O        H     H    210            O         CH.sub.2 Cl    H    211            CH.sub.2  O        Cl    H    212            O         CO       H     H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, and Z are hydrogen, W is    methyl; Y is fluoro; and X is:              Cmpd. No.       X    __________________________________________________________________________              213                               ##STR170##              214                               ##STR171##    __________________________________________________________________________    Where R.sup.1, R.sup.6, Y and Z are hydrogen, and W is methyl    Cmpd. No.  R.sup.2    R.sup.7    X    __________________________________________________________________________    215                ##STR172##                           ##STR173##                                      ##STR174##    216                ##STR175##                           ##STR176##                                      ##STR177##    217                ##STR178##                           ##STR179##                                      ##STR180##    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen; W is    1-methylethyl  i.e., CH(CH.sub.3).sub.2 !; and X is:              Cmpd. No.       X    __________________________________________________________________________              218                               ##STR181##              219                               ##STR182##    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y and Z are hydrogen    Cmpd. No.        W      X    __________________________________________________________________________    220              H                             ##STR183##    221              F                             ##STR184##    222              F                             ##STR185##    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7 and Z are hydrogen; W is methyl;    and X is:     ##STR186##    Cmpd. No.    A        B        D      E    __________________________________________________________________________    223          CH.sub.2 O        CH.sub.3                                          H    224          CH.sub.2 O        CF.sub.3                                          H    225          O        CH.sub.2 CH.sub.3                                          H    226          O        CH.sub.2 CF.sub.3                                          H    227          O        CO       Cl     H    228          O        CO       CH.sub.3                                          H    229          O        CO       CF.sub.3                                          H    230          CO       O        H      H    231          CO       O        Cl     H    232          CO       O        CH.sub.3                                          H    233          CO       O        CF.sub.3                                          H    234          O        O        H      H    235          O        O        Cl     H    236          O        O        F      H    237          O        O        CH.sub.3                                          H    238          O        O        CF.sub.3                                          H    239          O        CH.sub.2 F      H    240          O        CH.sub.2 H      OH    241          O        CH.sub.2 H      OCH.sub.3    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, W, Y, and Z are hydrogen; and X    is:     ##STR187##    Cmpd. No.    V.sup.4                        W.sup.4                               X.sup.4                                      Y.sup.4                                             Z.sup.4    __________________________________________________________________________    242          H      H      Cl     H      H    243          H      Cl     H      H      H    244          H      CF.sub.3                               H      CF.sub.3                                             H    245          H      CF.sub.3                               H      H      H    246          H      Cl     H      Cl     H    247          Cl     H      H      H      H    248          CF.sub.3                        H      H      H      Cl    249          H      H      CF.sub.3                                      H      H    250          Cl     H      H      H      Cl    __________________________________________________________________________    Where R.sup.1, R.sup.6, Y, and Z are hydrogen, and W is methyl    Cmpd. No.          R.sup.2        R.sup.7        X    __________________________________________________________________________    251           ##STR188##                          ##STR189##                                         ##STR190##    252           ##STR191##                          ##STR192##                                         ##STR193##    253           ##STR194##                          ##STR195##                                         ##STR196##    254           ##STR197##                          ##STR198##                                         ##STR199##    255           ##STR200##                          ##STR201##                                         ##STR202##    256           ##STR203##                          ##STR204##                                         ##STR205##    257           ##STR206##                          ##STR207##                                         ##STR208##    258           ##STR209##                          ##STR210##                                         ##STR211##    259           ##STR212##                          ##STR213##                                         ##STR214##    260           ##STR215##                          ##STR216##                                         ##STR217##    261           ##STR218##                          ##STR219##                                         ##STR220##    262           ##STR221##                          ##STR222##                                         ##STR223##    263           ##STR224##                          ##STR225##                                         ##STR226##    264           ##STR227##                          ##STR228##                                         ##STR229##    265           ##STR230##                          ##STR231##                                         ##STR232##    266           ##STR233##                          ##STR234##                                         ##STR235##    267           ##STR236##                          ##STR237##                                         ##STR238##    268           ##STR239##                          ##STR240##                                         ##STR241##    269           ##STR242##                          ##STR243##                                         ##STR244##    270           ##STR245##                          ##STR246##                                         ##STR247##    271           ##STR248##                          ##STR249##                                         ##STR250##    __________________________________________________________________________    Where Y and Z are hydrogen, W is methyl,    X is                  and                             R.sup.1 and R.sup.2 taken together, and                             R.sup.6 and R.sup.7 taken together form                             the group     ##STR251##                              ##STR252##           Cmpd. No.     R.sup.8      R.sup.9    __________________________________________________________________________           272           CH.sub.3     CH.sub.3           273           CH(CH.sub.3).sub.2                                      CH(CH.sub.3).sub.2           274           CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2    __________________________________________________________________________                         N    Where R.sup.1, R.sup.2, R.sup.6 and R.sup.7 are hydrogen    Cmpd. No.  W      X             Y         Z    __________________________________________________________________________    275        CH.sub.3                       ##STR253##   H HCl Salt                                              H    276        CH.sub.3                       ##STR254##   H Gluconic Acid Salt                                              H    277        CH.sub.3                       ##STR255##   H Ethane- sulfonic Acid Salt                                              H    278        CH.sub.3                       ##STR256##   H Pamoic Acid Salt                                              H    __________________________________________________________________________    Where R.sup.1, R.sup.2, R.sup.6, R.sup.7, Y, and Z are hydrogen, W is    methyl, and X is:     ##STR257##    Cmpd. No.    V.sup.4 W.sup.4                                X.sup.4 Y.sup.4                                             Z.sup.4    __________________________________________________________________________    279          Cl      H      H       H    H    280          H       Cl     H       H    H    281          H       H      Cl      H    H    282          CF.sub.3                         H      H       H    H    283          H       CF.sub.3                                H       H    H    284          H       H      CF.sub.3                                        H    H    __________________________________________________________________________     FOOTNOTES     .sup.1) In Compound 46, X is     ##STR258##     .sup.2 In Compounds 91-102, the left hand portion of the moiety Q, is     attached to the quinazoline ring.

                  TABLE 1-a    ______________________________________    Melting Points and Empirical Formulas of Compounds of Table 1    COMPOUND  MELTING POINT (°C.)                             EMPIRICAL FORMULA    ______________________________________    1         240-246        C.sub.8 H.sub.8 N.sub.4    2         186-188        C.sub.8 H.sub.7 ClN.sub.4    3         249-251        C.sub.8 H.sub.7 FN.sub.4    4         202-204        C.sub.8 H.sub.7 BrN.sub.4    5         192-193        C.sub.8 H.sub.7 lN.sub.4    6         264-270        C.sub.8 H.sub.7 ClN.sub.4    7         >360           C.sub.8 H.sub.11 Cl.sub.2 N.sub.5    8         264-266        C.sub.8 H.sub.7 BrN.sub.4    9         315-320        C.sub.8 H.sub.7 FN.sub.4    10        246-247        C.sub.8 H.sub.7 ClN.sub.4    11        255-256        C.sub.8 H.sub.7 BrN.sub.4    12        274-277        C.sub.8 H.sub.7 FN.sub.4    13        266-267        C.sub.8 H.sub.7 lN.sub.4    14        285-287        C.sub.8 H.sub.7 FN.sub.4    15        >320           C.sub.8 H.sub.6 Cl.sub.2 N.sub.4    16        >256           C.sub.8 H.sub.6 Br.sub.2 N.sub.4    17        256-257        C.sub.8 H.sub.6 F.sub.2 N.sub.4    18        172-173        C.sub.8 H.sub.6 F.sub.2 N.sub.4    19        295-296        C.sub.8 H.sub.6 F.sub.2 N.sub.4    20        273-275        C.sub.8 H.sub.6 BrClN.sub.4    21        >325           C.sub.8 H.sub.6 BrClN.sub.4    22        >325           C.sub.8 H.sub.6 BrClN.sub.4    23        287, dec.      C.sub.9 H.sub.6 ClN.sub.5    24        204-205        C.sub.8 H.sub.8 ClN.sub.5    25        188-198        C.sub.8 H.sub.5 Br.sub.2 ClN.sub.4    26        215-220        C.sub.8 H.sub.4 F.sub.4 N.sub.4    27        210-212        C.sub.9 H.sub.10 N.sub.4    28        250-253        C.sub.9 H.sub.10 N.sub.4    29        226-227        C.sub.9 H.sub.10 N.sub.4    30        228, dec.      C.sub.9 H.sub.9 N.sub.5 O.sub.2    31        293, dec.      C.sub.9 H.sub.9 N.sub.5 O.sub.2    32        219-222        C.sub.9 H.sub.11 N.sub.5    33        176-178        C.sub.9 H.sub.7 F.sub.3 N.sub.4    34        234-236        C.sub.9 H.sub.7 F.sub.3 N.sub.4    35        244-246        C.sub.9 H.sub.7 F.sub.3 N.sub.4    36        214-216        C.sub.10 H.sub.12 N.sub.4 O    37        245-246        C.sub.10 H.sub.9 F.sub.3 N.sub.4 O    38        255-258        C.sub.8 H.sub.9 N.sub.5    40        231-232        C.sub.9 H.sub.7 N.sub.5    41        249-259        C.sub.14 H.sub.12 N.sub.4    42        244 partial, 255-257                             C.sub.14 H.sub.12 N.sub.4    43        254-258        C.sub.14 H.sub.12 N.sub.4    44        287-290        C.sub.18 H.sub.20 N.sub.4    45        256-259        C.sub.16 H.sub.10 F.sub.6 N.sub.4    46        208-210, dec.  C.sub.22 H.sub.24 N.sub.6 O.sub.5    47        248-251        C.sub.14 H.sub.11 ClN.sub.4    48        256-259        C.sub.14 H.sub.10 Cl.sub.2 N.sub.4    49        268-280        C.sub.14 H.sub.10 ClFN.sub.4    50        238-240        C.sub.14 H.sub.9 Cl.sub.3 N.sub.4    51        245-250        C.sub.15 H.sub.13 Cl.sub.3 N.sub.4 O    52        222-225        C.sub.14 H.sub.9 Cl.sub.2 FN.sub.4    53        >280           C.sub.16 H.sub.9 ClF.sub.6 N.sub.4    54        224-229        C.sub.18 H.sub.13 ClN.sub.4    55        264-268        C.sub.14 H.sub.11 ClN.sub.4    56        230-238, dec.  C.sub.14 H.sub.11 ClN.sub.4    57        115-125        C.sub.20 H.sub.16 N.sub.4    58        250-258, dec.  C.sub.20 H.sub.18 N.sub.4 O    59        238-242. dec.  C.sub.20 H.sub.15 ClN.sub.4    60        245-247        C.sub.16 H.sub.16 N.sub.4    61        251-253        C.sub.18 H.sub.22 N.sub.4 O    62        308-311, dec.  C.sub.19 H.sub.22 N.sub.4    63        222-225        C.sub.17 H.sub.12 F.sub.6 N.sub.4    64        187-191        C.sub.24 H.sub.12 F.sub.12 N.sub.4    65        --             C.sub.14 H.sub.10 Cl.sub.2 N.sub.4 O    66        --             C.sub.15 H.sub.12 Cl.sub.2 N.sub.4 O    67        157-162        C.sub.19 H.sub.20 Cl.sub.2 N.sub.4 O    68        --             C.sub.25 H.sub.32 Cl.sub.2 N.sub.4 O    69        180-183        C.sub.18 H.sub.29 Cl.sub.2 N.sub.4 O    70        --             C.sub.21 H.sub.15 Cl.sub.3 N.sub.4 OSi    71        --             C.sub.24 H.sub.21 Cl.sub.3 N.sub.4 O    72         97-110        C.sub.21 H.sub.11 Cl.sub.2 F.sub.5 N.sub.4 O    73        112-120        C.sub.20 H.sub.15 Cl.sub.2 N.sub.5 O    74        105-112        C.sub.25 H.sub.24 Cl.sub.2 N.sub.4 O.sub.4 S    75        232-234        C.sub.14 H.sub.10 ClN.sub.4 O    76        268-270        C.sub.14 H.sub.10 Cl.sub.2 N.sub.4 O.sub.2 S    77        197-199        C.sub.15 H.sub.12 N.sub.4 S    78        200-205        C.sub.15 H.sub.12 N.sub.4 S    79        178-180        C.sub.16 H.sub.16 N.sub.4    80        232-234        C.sub.14 H.sub.10 Cl.sub.2 N.sub.4 S    81        >250           C.sub.14 H.sub.10 Cl.sub.2 N.sub.4 OS    82        286-289        C.sub.14 H.sub.10 Cl.sub.2 N.sub.4 O.sub.2 S    83          227-229.5    C.sub.20 H.sub.18 N.sub.4    84        223-224        C.sub.20 H.sub.16 N.sub.4    85        257-258, dec.  C.sub.20 H.sub.16 N.sub.4    86          218-219.5    C.sub.18 H.sub.14 N.sub.4 S    87        217-219        C.sub.18 H.sub.14 N.sub.4 OS    88        235-237        C.sub.18 H.sub.14 N.sub.4 S    89        312-314        C.sub.18 H.sub.14 N.sub.4 OS    90        300-302        C.sub.18 H.sub.14 N.sub.4 O.sub.2 S    91        234-235        C.sub.18 H.sub.18 ClN.sub.5 O.sub.3    92        115-117        C.sub.19 H.sub.24 ClN.sub.5 O.sub.4    93         95-210        C.sub.21 H.sub.29 N.sub.5 O.sub.6    94        195, dec.      C.sub.19 H.sub.23 Cl.sub.2 N.sub.5 O.sub.5    95          147-148.5    C.sub.21 H.sub.25 N.sub.5 O.sub.5    96        204            C.sub.20 H.sub.25 ClN.sub.5 O.sub.5    97        70-72          C.sub.22 H.sub.27 N.sub.5 O.sub.5    98        205, dec.      C.sub.21 H.sub.27 Cl.sub.2 N.sub.5 O.sub.5    99        120-125        C.sub.23 H.sub.29 N.sub.5 O.sub.5    100       190-191        C.sub.22 H.sub.26 ClN.sub.5 O.sub.5    101       210, dec.      C.sub.21 H.sub.27 Cl.sub.2 N.sub.5 O.sub.5    102       169-171        C.sub.23 H.sub.29 N.sub.5 O.sub.5    103       223-225        C.sub.8 H.sub.6 F.sub.2 N.sub.4    104       265-267        C.sub.8 H.sub.6 ClFN.sub.4    105       295, dec.      C.sub.8 H.sub.6 ClFN.sub.4    106       240-245        C.sub.14 H.sub.11 ClN.sub.4    107       277-278        C.sub.16 H.sub.16 N.sub.4    108       282-285        C.sub.18 H.sub.20 N.sub.4    109       235-237        C.sub.15 H.sub.11 F.sub.3 N.sub.4    110       207            C.sub.15 H.sub.14 N.sub.4 O    111       203-206        C.sub.16 H.sub.13 F.sub.3 N.sub.4 O    112       >250           C.sub.15 H.sub.14 N.sub.4    113       225-229        C.sub.15 H.sub.13 ClN.sub.4    114       >250           C.sub.15 H.sub.13 ClN.sub.4    115       >250           C.sub.15 H.sub.13 FN.sub.4    116       >250           C.sub.15 H.sub.12 Cl.sub.2 N.sub.4    117       >250           C.sub.15 H.sub.12 ClFN.sub.4    118       >250           C.sub.16 H.sub.16 N.sub.4    119       >250           C.sub.16 H.sub.16 N.sub.4    120       >250           C.sub.17 H.sub.18 N.sub.4    121       239-241        C.sub.16 H.sub.15 ClN.sub.4 O    122       >250           C.sub.17 H.sub.18 N.sub.4    123       >250           C.sub.18 H.sub.20 N.sub.4    124       208-210        C.sub.16 H.sub.13 F.sub.3 N.sub.4    125       224-226        C.sub.16 H.sub.13 F.sub.3 N.sub.4    126       232-235        C.sub.16 H.sub.13 F.sub.3 N.sub.4    127       185-190        C.sub.19 H.sub.13 F.sub.9 N.sub.4    128       >250           C.sub.17 H.sub.18 N.sub.4 O    129       >250           C.sub.18 H.sub.20 N.sub.4 O    130       >250           C.sub.18 H.sub.20 N.sub.4 O    131       238-244        C.sub.17 H.sub.18 N.sub.4 O    132       >250           C.sub.16 H.sub.13 F.sub.3 N.sub.4 O    133       265-270        C.sub.16 H.sub.13 N.sub.5    134       >250           C.sub.15 H.sub.13 N.sub.5 O.sub.2    135       279-283        C.sub.16 H.sub.15 N.sub.5 O    136       >250           C.sub.19 H.sub.21 N.sub.5 O    137       274-275        C.sub.16 H.sub.17 N.sub.5 O.sub.2 S    138       263-268        C.sub.21 H.sub.18 N.sub.4    139       197-201        C.sub.17 H.sub.18 N.sub.4    140       209-212        C.sub.18 H.sub.17 F.sub.3 N.sub.4    141       122-123        C.sub.19 H.sub.16 F.sub.6 N.sub.4    142       >300           C.sub.17 H.sub.15 ClN.sub.4    143       >300           C.sub.18 H.sub.14 ClF.sub.3 N.sub.4    144       >350           C.sub.19 H.sub.13 ClF.sub.6 N.sub.4    145       293-295        C.sub.13 H.sub.12 N.sub.4 S    146       270-272        C.sub.13 H.sub.11 ClN.sub.4 S    147       258-260        C.sub.14 H.sub.14 N.sub.4 S    148       202-204        C.sub.16 H.sub.10 F.sub.6 N.sub.4    149       --             C.sub.15 H.sub.12 N.sub.4 O    150       --             C.sub.15 H.sub.11 ClN.sub.4 O    151       --             C.sub.15 H.sub.11 ClN.sub.4 O    152       --             C.sub.15 H.sub.10 Cl.sub.2 N.sub.4 O    153       --             C.sub.15 H.sub.10 Cl.sub.2 N.sub.4 O    154       --             C.sub.15 H.sub.11 ClN.sub.4 O    155       --             C.sub.16 H.sub.11 F.sub.3 N.sub.4 O    156       --             C.sub.16 H.sub.11 F.sub.3 N.sub.4 O    157       --             C.sub.17 H.sub.10 F.sub.6 N.sub.4 O    158       --             C.sub.16 H.sub.11 F.sub.3 N.sub.4 O    159       --             C.sub.17 H.sub.14 N.sub.4 O.sub.3    160       --             C.sub.15 H.sub.11 FN.sub.4 O    161       --             C.sub.17 H.sub.14 N.sub.4 O.sub.3    162       --             C.sub.15 H.sub.11 FN.sub.4 O    163       --             C.sub.15 H.sub.11 FN.sub.4 O    164       --             C.sub.15 H.sub.10 F.sub.2 N.sub.4 O    165       --             C.sub.15 H.sub.11 FN.sub.4 O    166       --             C.sub.15 H.sub.11 FN.sub.4 O    167       --             C.sub.15 H.sub.9 F.sub.3 N.sub.4 O    168       --             C.sub.21 H.sub.15 FN.sub.4 O    169       --             C.sub.21 H.sub.15 ClN.sub.4 O    170       --             C.sub.22 H.sub.15 F.sub.3 N.sub.4 O    171       --             C.sub.21 H.sub.15 FN.sub.4 O    172       --             C.sub.21 H.sub.15 ClN.sub.4 O    173       --             C.sub.22 H.sub.15 F.sub.3 N.sub.4 O    174       238-240, dec.  C.sub.16 H.sub.13 Cl.sub.2 N.sub.5 O    175       248-250, dec.  C.sub.16 H.sub.12 Cl.sub.3 N.sub.5 O    176       --             C.sub.17 H.sub.13 F.sub.3 N.sub.4 O.sub.2    177       --             C.sub.18 H.sub.15 F.sub.3 N.sub.4 O.sub.2    178       --             C.sub.15 H.sub.12 F.sub.2 N.sub.4    179       315-320, dec.  C.sub.18 H.sub.19 F.sub.3 N.sub.4 O.sub.3 S    180       257-262        C.sub.16 H.sub.16 N.sub.4 S    181       248            C.sub.17 H.sub.18 N.sub.4 S    182       325-330        C.sub.18 H.sub.14 ClF.sub.3 N.sub.4    183       314-320, Dec.  C.sub.17 H.sub.19 ClN.sub.4 O.sub.3 S    184       279            C.sub.17 H.sub.18 N.sub.4 O.sub.2 S    185       188-192        C.sub.19 H.sub.22 N.sub.4 S    186       235-237        C.sub.19 H.sub.22 N.sub.4 O.sub.2 S    187       252-254        C.sub.16 H.sub.15 ClN.sub.4 O    188       225-226        C.sub.16 H.sub.12 F.sub.4 N.sub.4    189       >350           C.sub.17 H.sub.13 F.sub.3 N.sub.4 O    190       245-248        C.sub.21 H.sub.18 N.sub.4    191       --             C.sub.21 H.sub.17 ClN.sub.4    192       >250           C.sub.21 H.sub.16 F.sub.2 N.sub.4    193       >250           C.sub.21 H.sub.16 F.sub.2 N.sub.4    194       --             C.sub.22 H.sub.17 F.sub.3 N.sub.4    195       >230           C.sub.21 H.sub.17 ClN.sub.4    196       --             C.sub.21 H.sub.17 FN.sub.4    197       195-199        C.sub.22 H.sub.17 F.sub.3 N.sub.4    198       197-200        C.sub.21 H.sub.16 ClFN.sub.4    199       198-200        C.sub.21 H.sub.16 F.sub.2 N.sub.4    200       --             C.sub.22 H.sub.20 N.sub.4    201       260            C.sub.22 H.sub.19 ClN.sub.4    202       257            C.sub.22 H.sub.19 FN.sub.4    203       --             C.sub.22 H.sub.19 F.sub.3 N.sub.4    204       217            C.sub.21 H.sub.18 N.sub.4 O    205       202            C.sub.21 H.sub.17 ClN.sub.4 O    206       209            C.sub.21 H.sub.17 FN.sub.4 O    207       217-218        C.sub.21 H.sub.16 F.sub.2 N.sub.4 O    208       240-244        C.sub.19 H.sub.20 N.sub.4 O    209       207-210        C.sub.19 H.sub.20 N.sub.4 O    210       257-263        C.sub.19 H.sub.19 ClN.sub.4 O    211       259-262        C.sub.19 H.sub.19 ClN.sub.4 O    212       --             C.sub.19 H.sub.18 N.sub.4 O.sub.2    213       242-246        C.sub.15 H.sub.11 F.sub.3 N.sub.4    214       224-225        C.sub.17 H.sub.11 F.sub.7 N.sub.4    215       Oil            C.sub.21 H.sub.16 F.sub.6 N.sub.4 O.sub.2    216       225-226        C.sub.27 H.sub.28 F.sub.6 N.sub.4 O.sub.2    217       >250           C.sub.27 H.sub.28 F.sub.6 N.sub.4 O.sub.4    218       251-252        C.sub.17 H.sub.16 F.sub.2 N.sub.4    219       212-214        C.sub.19 H.sub.16 F.sub.6 N.sub.4    220       --             C.sub.23 H.sub.23 N.sub.5 OS    221       --             C.sub.16 H.sub.14 FN.sub.5 O.sub.2    222       --             C.sub.17 H.sub.16 FN.sub.5 O.sub.2    223       --             C.sub.20 H.sub.22 N.sub.4 O    224       --             C.sub.20 H.sub.19 F.sub.3 N.sub.4 O    225       254-256        C.sub.20 H.sub.22 N.sub.4 O    226       256-260        C.sub.20 H.sub.19 F.sub.3 N.sub.4 O    227       --             C.sub.19 H.sub.17 ClN.sub.4 O.sub.2    228       --             C.sub.20 H.sub.20 N.sub.4 O.sub.2    229       --             C.sub.20 H.sub.17 F.sub.3 N.sub.4 O.sub.2    230       --             C.sub.19 H.sub.18 N.sub.4 O.sub.2    231       268-270        C.sub.19 H.sub.17 ClN.sub.4 O.sub.2    232       --             C.sub.20 H.sub.20 N.sub.4 O.sub.2    233       --             C.sub.20 H.sub.17 F.sub.3 N.sub.4 O.sub.2    234       130-135        C.sub.18 H.sub.18 N.sub.4 O.sub.2    235       235-238        C.sub.18 H.sub.17 ClN.sub.4 O.sub.2    236       207-210        C.sub.18 H.sub.17 FN.sub.4 O.sub.2    237       --             C.sub.19 H.sub.20 N.sub.4 O.sub.2    238       --             C.sub.19 H.sub.17 F.sub.3 N.sub.4 O.sub.2    239       224-229        C.sub.19 H.sub.19 FN.sub.4 O    240       275 DEC        C.sub.19 H.sub.20 N.sub.4 O.sub.2    241       307-310        C.sub.20 H.sub.22 N.sub.4 O.sub.2    242       226-228        C.sub.14 H.sub.11 ClN.sub.4 O    243       218-220        C.sub.14 H.sub.11 ClN.sub.4 O    244       >200           C.sub.16 H.sub.10 F.sub.6 N.sub.4 O    245       158-160        C.sub.15 H.sub.11 F.sub.3 N.sub.4 O    246       >220           C.sub.14 H.sub.10 Cl.sub.2 N.sub.4 O    247       --             C.sub.14 H.sub.11 ClN.sub.4 O    248       --             C.sub.15 H.sub.11 F.sub.3 N.sub.4 O    249       --             C.sub.15 H.sub.11 F.sub.3 N.sub.4 O    250       --             C.sub.14 H.sub.10 Cl.sub.2 N.sub.4 O    251       240-245        C.sub.25 H.sub.28 Cl.sub.2 N.sub.4 O.sub.2    252       145-150        C.sub.23 H.sub.10 Cl.sub.2 F.sub.14 N.sub.4                             O.sub.2    253       135-140        C.sub.27 H.sub.32 Cl.sub.2 N.sub.4 O.sub.2    254       173-176        C.sub.21 H.sub.10 Cl.sub.2 F.sub.10 N.sub.4                             O.sub.2    255       121-124        C.sub.33 H.sub.44 Cl.sub.2 N.sub.4 O.sub.2    256       >200           C.sub.23 H.sub.24 Cl.sub.2 N.sub.4 O.sub.2    257       101            C.sub.39 H.sub.56 Cl.sub.2 N.sub.4 O.sub.2    258       177-180        C.sub.19 H.sub.16 Cl.sub.2 N.sub.4 O.sub.2    259       SOLID          C.sub.29 H.sub.18 Cl.sub.4 N.sub.4 O.sub.2    260       187-189        C.sub.31 H.sub.20 F.sub.6 N.sub.4 O.sub.2    261       011            C.sub.35 H.sub.44 F.sub.6 N.sub.4 O.sub.2    262       216-217        C.sub.25 H.sub.24 F.sub.6 N.sub.4 O.sub.2    263       85-90          C.sub.23 H.sub.10 F.sub.16 N.sub.4 O.sub.2    264       SOLID          C.sub.25 H.sub.24 F.sub.6 N.sub.4 O.sub.4    265       158-159        C.sub.29 H.sub.32 F.sub.6 N.sub.4 O.sub.2    266       152-153        C.sub.27 H.sub.28 F.sub.6 N.sub.4 O.sub.4    267       OIL            C.sub.31 H.sub.36 F.sub.6 N.sub.4 O.sub.8    268       --             C.sub.25 H.sub.16 F.sub.6 N.sub.4 O.sub.2    269       --             C.sub.23 H.sub.20 F.sub.6 N.sub.4 O.sub.6                             S.sub.2    270       76-78          C.sub.29 H.sub.32 F.sub.6 N.sub.4 O.sub.6    271       --             C.sub.31 H.sub.36 F.sub.6 N.sub.4 O.sub.6    272       208-210        C.sub.23 H.sub.22 F.sub.6 N.sub.6    273       --             C.sub.31 H.sub.38 F.sub.6 N.sub.6    274       --             C.sub.29 H.sub.30 F.sub.6 N.sub.6    275       --             C.sub.17 H.sub.13 F.sub.6 N.sub.4.HCl    276       164-166 DEC    C.sub.17 H.sub.13 F.sub.6 N.sub.4.C.sub.6                             H.sub.11 O.sub.7    277       --             C.sub.17 H.sub.13 F.sub.6 N.sub.4.C.sub.2                             H.sub.5 SO.sub.3 H    278       --             C.sub.17 H.sub.13 F.sub.6 N.sub.4.2C.sub.23                             H.sub.16 O.sub.6    279       --             C.sub.15 H.sub.13 ClN.sub.4 O    280       --             C.sub.15 H.sub.13 ClN.sub.4 O    281       >200 C         C.sub.15 H.sub.13 ClN.sub.4 O    282       --             C.sub.16 H.sub.13 F.sub.3 N.sub.4 O    283       --             C.sub.16 H.sub.13 F.sub.3 N.sub.4 O    284       --             C.sub.16 H.sub.13 F.sub.3 N.sub.4 O    ______________________________________

Insecticide Formulations

In the normal use of the insecticidal quinazolines of the presentinvention, they usually will not be employed free from admixture ordilution, but ordinarily will be used in a suitable formulatedcomposition compatible with the method of application and comprising aninsecticidally effective amount of the quinazoline. The quinazolines ofthis invention, like most pesticidal agents, may be blended with theagriculturally acceptable surface-active agents and carriers normallyemployed for facilitating the dispersion of active ingredients,recognizing the accepted fact that the formulation and mode ofapplication of an insecticide may affect the activity of the material.The present quinazolines may be applied, for example, as sprays, dusts,or granules to the area where pest control is desired, the type ofapplication varying of course with the pest and the environment. Thus,the quinazolines of this invention may be formulated as granules oflarge particle size, as powdery dusts, as wettable powders, asemulsifiable concentrates, as solutions, and the like. It will beunderstood that the insecticides themselves may be present asessentially pure compounds, or as mixtures of these quinazolinecompounds.

Granules may comprise porous or nonporous particles, such as attapulgiteclay or sand, for example, which serve as carriers for the quinazolines.The granule particles are relatively large, a diameter of about 400-2500microns typically. The particles are either impregnated with thequinazoline from solution or coated with the quinazoline, adhesivesometimes being employed. Granules generally contain 0.05-10%,preferably 0.5-5%, active ingredient as the insecticidally effectiveamount.

Dusts are admixtures of the quinazolines with finely divided solids suchas talc, attapulgite clay, kieselguhr, pyrophyllite, chalk, diatomaceousearths, calcium phosphates, calcium and magnesium carbonates, sulfur,flours, and other organic and inorganic solids which acts carriers forthe insecticide. These finely divided solids have an average particlesize of less than about 50 microns. A typical dust formulation usefulfor controlling insects contains 1 part of 2,4-diamino-5-methyl-6-3,5-di(trifluoromethyl)phenyl!quinazoline (Compound 63) and 99 parts oftalc.

The quinazolines of the present invention may be made into liquidconcentrates by dissolution or emulsification in suitable liquids andinto solid concentrates by admixture with talc, clays, and other knownsolid carriers used in the pesticide art. The concentrates arecompositions containing, as an insecticidally effective amount, about5-50% quinazoline, and 95-50% inert material, which includessurface-active dispersing, emulsifying, and wetting agents, but evenhigher concentrations of active ingredient may be employedexperimentally. The concentrates are diluted with water or other liquidsfor practical application as sprays, or with additional solid carrierfor use as dusts.

By way of illustration, compound 63 was formulated as a 10% wettablepowder (10% WP) as follows:

    ______________________________________    COMPONENT        AMOUNT (wt/wt)    ______________________________________    Compound 63      10.1%    Wetting Agent    5.0%    Dispersing Agent 3.8%    Wetting/Dispersing Agent                     0.9%    Diluent          80.2%    ______________________________________

Manufacturing concentrates are useful for shipping low melting productsof this invention. Such concentrates are prepared by melting the lowmelting solid products together with one percent or more of a solvent toproduce a concentrate which does not solidify on cooling to the freezingpoint of the pure product or below.

Useful liquid concentrates include the emulsifiable concentrates, whichare homogeneous liquid or paste compositions readily dispersed in wateror other liquid carriers. They may consist entirely of the quinazolineswith a liquid or solid emulsifying agent, or they may also contain aliquid carrier such as xylene, heavy aromatic naphthas, isophorone andother relatively non-volatile organic solvents. For application, theseconcentrates are dispersed in water or other liquid carriers andnormally applied as sprays to areas to be treated.

Typical surface-active wetting, dispersing, and emulsifying agents usedin pesticidal formulations include, for example, the alkyl and alkylarylsulfonates and sulfates and their sodium salts, including fatty methyltaurides; alkylaryl polyether alcohols; sulfates of higher alcohols;polyvinyl alcohols; polyethylene oxides; sulfonated animal and vegetableoils; sulfonated petroleum oils; fatty acid esters of polyhydricalcohols and the ethylene oxide addition products of such esters; andthe addition products of long-chain mercaptans and ethylene oxide. Manyother types of useful surface-active agents are available in commerce.The surface-active agent, when used, normally comprises about 1-15% byweight of the insecticidal composition.

Other useful formulations include simple solutions of the activeingredient in a solvent in which it is completely soluble at the desiredconcentrations, such as acetone or other organic solvents.

As shown in the biological test methods below, the compounds of thepresent invention were tested in the laboratory as dimethylsulfoxidesolutions incorporated into an artificial insect diet or as aqueousacetone or methanol solutions containing a small amount ofoctylphenoxypolyethoxyethanol surfactant for use as foliar sprays. Aninsecticidally effective amount of quinazoline in an insecticidalcomposition diluted for application is normally in the range of about0.001% to about 8% by weight. Many variations of spraying and dustingcompositions known in the art may be used by substituting thequinazoline of this invention into compositions known or apparent in theart.

The insecticidal compositions of this invention may be formulated withother active ingredients, including other insecticides, nematicides,acaricides, fungicides, plant growth regulators, fertilizers, etc.

In using the compositions to control insects, it is only necessary thatan insecticidally effective amount of quinazoline be applied to thelocus where control is desired. Such locus may, e.g., be the insectsthemselves, plants upon which the insects feed, or the insect habitat.When the locus is the soil, e.g., soil in which agricultural crops areor will be planted, the active compound may be applied to and optionallyincorporated into the soil. For most applications, an insecticidallyeffective amount will be about 75 to 4000 g per hectare, preferably 150g to 3000 g per hectare.

Biological Data

The substituted 2,4-diaminoquinazolines of the present invention wereincorporated into an artificial diet for evaluation of insecticidalactivity against the tobacco budworm (Heliothis virescens Fabricius!).

Stock solution s of test chemical in dimethyl sulfoxide were prepa redfor each rate of application. The rates of application, expressed as thenegative log of the mol ar con centration , and the correspondingconcentrations of the stock solution prepared for each rate are shownbelow:

    ______________________________________    Stock Solution                  Rate of Application    ______________________________________    50 micromolar 4    5             5    0.5           6    0.05          7    0.005         8    ______________________________________

One hundred microliters of each of the stock solutions was manuallystirred into 50 mL of a molten (65°-70° C.) wheat germ-based artificialdiet. The 50 mL of molten diet containing the test chemical was pouredevenly into twenty wells in the outer four rows of a twenty-five well,five row plastic tray. Each well in the tray was about 1 cm in depth,with an opening of 3 cm by 4 cm at the lip. Molten diet containing onlydimethyl sulfoxide at the levels used in the test chemical-treated dietwas poured into the five wells in the third row of the tray. Each traytherefore contained one test chemical at a single rate of application,together with an untreated control.

Single second instar tobacco budworm larvae were placed in each well.The larvae were selected at a stage of growth at which they uniformlyweigh about 5 mg each. Upon completion of infestation, a sheet of clearplastic was heat-sealed over the top of the tray using a commonhousehold flat iron. The trays were held at 25° C. at 60% relativehumidity for five days in a growth chamber. Lighting was set at 14 hoursof light and 10 hours of darkness.

After the 5-day exposure period, mortality counts were taken, and thesurviving insects were weighed. From the weights of the survivinginsects that fed on the treated diet as compared to those insects thatfed on the untreated diet, the percent growth inhibition caused by eachtest chemical was determined. From these data, the negative log of theconcentration of the test chemical that provided 50% growth inhibition(pl₅₀) was determined by linear regression, when possible, for each testchemical. Where possible, the negative log of the concentration of thetest chemical that provided 50% mortality (pLC₅₀) was also determined.

Generally, the compounds of the present invention inhibited the growthof tobacco budworm. Amongst the most efficacious compounds wereCompounds 51-53, 61, 63, 66, 113, 115-117, 125, 128, 129, 143, and178-182 with pl₅₀ values of greater than 6.3. Compounds 53, 63, and 129,were highly active compounds with pl₅₀ values of greater than 6.7 All ofthe compounds exemplified above caused some insect mortality in thistest. These data are presented in Table 2.

Certain substituted-2,4-diaminoquinazoline derivatives with high pl₅₀values from the diet test were tested for insecticidal activity infoliar evaluations against the tobacco budworm, beet armyworm(Spodoptera exigua Hubner!), and the cabbage looper (Trichoplusia niHubner!).

In these tests against the tobacco budworm and the beet armyworm,nine-day-old chick pea plants (Cicer arietinum) were sprayed at 20 psito runoff on both upper and lower leaf surfaces with solutions of testchemical to provide application rates as high as 1000 ppm of testchemical. The solvent used to prepare the solutions of test chemical was10% acetone or methanol (v/v) and 0.1% of the surfactantoctylphenoxypolyethoxyethanol in distilled water. Four replicates, eachcontaining four chick pea plants, for each rate of application of testchemical were sprayed. The treated plants were transferred to a hoodwhere they were kept until the spray had dried.

The four chick pea plants in each replicate treated with test chemicalas described above were removed from their pots by cutting the stemsjust above the soil line. The excised leaves and stems from the fourplants in each replicate were placed in individual 8-ounce paper cups,which contained a moistened filter paper. Five second-instar (4-5 daysold) tobacco budworms or beet armyworms were counted into each cup,taking care not to cause injury. An opaque plastic lid was placed oneach cup, which was then held in a growth chamber for a 96 hour exposureperiod at 25° C. and 50% relative humidity. At the end of the 96 hourexposure period the cups were opened, and the numbers of dead and liveinsects were counted. Moribund larvae which were disoriented or unableto crawl normally were counted as dead. Using the insect counts, theefficacy of the test chemical was expressed in percent mortality. Thecondition of the test plants was also observed for phytotoxicity and forreduction of feeding damage as compared to an untreated control. Whereapplicable, computer-generated LC₅₀ values were determined from thepercentages of insect mortality.

Foliar tests with cabbage looper were conducted in the same manner asdescribed above, the difference being that pinto bean plants (Phaseolusvulgaris) were used.

Of the compounds evaluated on foliage for insecticidal activity, themore active ones included Compounds 63, 113, 116, 143, 178, 183, 188,207, 208, 210, 218, 219, 225, 226, 235, 239, 256, and 258 of Table 1.

                  TABLE 2    ______________________________________    Insecticidal Activity of Substituted-2,4-diaminoquinazolines    Incorporated    into the Diet of Tobacco Budworm            Rate of   Percent Growth  Percent    Cmpd. No.            Application.sup.1                      Inhibition.sup.2,3,4                                 pl.sub.50.sup.5                                      Mortality.sup.6                                             pLC.sub.50.sup.7    ______________________________________    2       8         ND         <4.0 0      --            7         ND              0            6         -20             0            5         -11             0            4         33              20    3       4         7          --   0      --    4       5         13         --   0      --    5       5         -14        <4.0 0      --    8       4         21         <4.0 0      --    9       4         5          --   0      --    10      4         1          --   0      --    11      4         -3         --   0      --    12      4         -12        --   0      --    13      4         -4         --   0      --    14      4         -18        --   0      --    16      4         5          --   0      --    17      4         -15        --   0      --    19      4         -8         --   0      --    20      7         ND         4.5  0      --            6         9               0            5         15              0            4         84              15    21      4         23         <4.0 0      --    22      4         -2         --   0      --    25      7         ND         --   0      --            6         ND              0            5         7               0            4         12              0    26      4         17         --   0      --    27      5         14         --   0      --            4         20              0    28      4         12         --   0      --    29      4         -7         --   0      --    30      4         42         <4.0 0      --    31      4         8          --   0      --    33      4         13         --   0      --    34      4         31         <4.0 0      --    36      4         7          --   0      --    37      4         23         <4.0 0      --    38      4         -4         --   0      --    39      4         TRACE      --   0      --    40      4         9          --   0      --    41      4         4          --   0      --    42      6         -4         --   0      --            5         10              0            4         17              0    45      6         -2         4.9  0      --            5         56              0            4         82              0    46      5         4          4.4  0      --            4         82              0    47      7         20         5.0  0      --            6         15              0            5         54              0            4         84              0    48      8         20         6.3  0      --            7         26              0            6         63              10            5         93              50            4         100             85    49      7         -6         6.1  0      4.5            6         63              5            5         98              45            4         97              60    50      7         -5         5.3  0      <4.0            6         23              0            5         68              10            4         93              40            8         1          5.8  0      <4.0            7         0               0            6         47              0            5         83              20            4         92              30    51      7         7          6.5  0      5.6            6         88              20            5         99              90            4         100             95            8         5          6.8  0      5.4            7         25              0            6         87              35            5         97              65            4         99              85    52      7         -8         6.4  0      <4.0            6         93              10            5         95              25            4         97              45            7         32         6.7  0      5.8            6         93              30            5         100             95            4         100             95    53      7         46         6.9  10     5.6            6         90              25            5         100             95            4         100             95    54      7         9          6.1  0      <4.0            6         64              5            5         94              25            4         96              35    55      4         21         <4.0 0      --    56      4         6          --   0      --    58      4         16         --   0      --    59      4         24         <4.0 0      --    60      7         7          6.1  0      4.6            6         63              5            5         95              25            4         99              75    61      8         9          6.7  0      <4.0            7         49              0            6         78              5            5         92              10            4         96              35            8         -6         6.5  0      4.0            7         36              0            6         79              15            5         96              20            4         99              50    62      5         32         4.2  0      --            4         54              0    63      7         5          5.9  0      --            6         41              0            5         86              0            4         96              15            7         81         >7.0 55     >7.0            6         94              60            5         100             95            4         100             95    64      6         -2         4.8  0      --            5         34              0            4         93              0    65      5         6          --   0      --            4         3               5    66      7         36         6.7  0      --            6         82              0            5         92              0            4         97              20            8         2          6.5  0      <4.0            7         19              0            6         84              0            5         94              0            4         98              35            8         7          6.7  0      <4.0            7         24              0            6         83              0            5         94              5            4         99              45    67      6         16         5.0  0      --            5         46              0            4         86              10    68      6         0          5.0  0      <4.0            5         53              0            4         94              35            6         3          4.9  0      <4.0            5         44              0            4         94              25    69      6         34         5.2  0      --            5         50              0            4         86              5    70      6         15         5.5  0      4.3            5         85              0            4         99         75    71      6         -8         4.7  0      --            5         48              0            4         70              0            6         5          4.3  0      --            5         9               0            4         65              0    72      6         1          5.1  0      --            5         72              0            4         95              25    73      6         58         --   0      --            5         89              5            4         95              10            7         7          6.1  0      --            6         71              0            5         91              0            4         94              15    74      7         3          5.0  0      --            6         6               0            5         59              0            4         87              5    75      5         14         <4.0 0      --            4         34              0    76      4         16         --   0      --    77      6         3          4.4  0      <4.0            5         13              0            4         75              30    78      6         27         4.6  0      --            5         33              0            4         63              0    79      5         14         4.1  0      --            4         56              0    80      5         30         4.7  0      --            4         89              20    81      6         -7         4.7  0      --            5         28              0            4         91              20    82      8         23         5.8  5      4.9            7         15              0            6         28              0            5         84              40            4         97              95            7         12         5.5  0      4.0            6         11              0            5         87              5            4         97              50    83      6         9          4.7  0      --            5         25              0            4         77              5    84      6         19         4.3  0      --            5         20              0            4         56              5    85      4         -6         --   0      --    86      6         16         <4.0 0      --            5         15              0            4         30              0    87      4         -6         --   0      --    88      6         -28        4.8  0      --            5         47              0            4         88              15            6         15         5.0  0      --            5         46              0            4         85              10    89      6         19         5.0  0      --            5         49              0            4         87              0    90      7         23         5.3  0      --            6         26              0            5         69              0            4         84              10    91      6         39         4.7  0      --            5         36              0            4         88              10    92      7         14         5.8  0      --            6         27              0            5         82              0            4         93              15    93      6         3          4.8  0      --            5         39              5            4         85              10    94      4         2          --   0      --    95      4         13         --   0      --    96      4         -3         --   0      --    97      4         29         <4.0 0      --    98      4         7          --   0      --    99      4         -7         --   0      --    100     5         -6         <4.0 0      --            4         33              0    101     4         17         --   0      --    102     4         14         --   0      --    106     5         -1         4.3  0      --            4         71              0    107     6         2          5.0  0      --            5         57              0            4         85              5    108     7         6          4.6  0      --            6         20              0            5         28              0            4         79              0    109     6         -3         4.7  0      --            5         68              5            4         92    110     5         1          <4.0 0      --            4         43              5    111     5         5          4.3  0      --            4         68              10    112     6         24         5.6  0      <4.0            5         85              20            4         97              25    113     7         17         6.5  0      5.2            6         86              10            5         98              60            4         98              55    114     6         10         5.2  0      4.2            5         69              25            4         97              55    115     7         28         6.4  0      4.4            6         68              5            5         97              35            4         99              60    116     7         27         6.4  0      5.4            6         65              5            5         99              80            4         100             95    117     7         29         6.4  0      4.5            6         70              0            5         95              20            4         100             75    118     7         23         6.1  0      --            6         48              0            5         92              0            4         96              15    119     6         10         4.7  0      --            5         39              0            4         75              15    121     7         6          6.2  0      4.6            6         76              0            5         97              35            4         99              70    122     6         40         5.8  0      --            5         96              20            4         89              20    123     7         21         6.2  0      <4.0            6         59              0            5         91              5            4         97              40            7         0          6.0  0      --            6         61              0            5         91              0            4         97              5    124     6         7          --   0      <4.0            5         96              25            4         97              35            8         -16        6.2  0      4.5            7         21              0            6         62              5            5         92              25            4         99              70    125     8         17         6.9  0      5.5            7         37              0            6         89              10            5         100             85            4         100             90    126     6         -5         5.0  0      --            5         57              0            4         96              20    127     6         69         >6.0 0      <4.0            5         94              20            4         96              40            7         5          6.2  0      4.7            6         77              10            5         96              40            4         99              70    128     7         22         6.6  5      4.6            6         85              15            5         96              25            4         99              70    129     7         44         6.8  0      <4.0            6         76              15            5         97              25            4         98              45    130     5         6          4.4  0      --            4         76              10    131     7         2          5.9  0      --            6         54              0            5         85              0            4         94              20    132     7         -8         6.0  0      4.4            6         60              15            5         92              25            4         99              70    133     7         -1         5.8  0      4.0            6         31              5            5         91              20            4         96              50    134     6         13         5.3  0      <4.0            5         78              5            4         98              35    135     6         -6         4.9  0      --            5         52              0            4         90              15    136     6         4          4.9  0      <4.0            5         47              10            4         91              30    137     6         1          4.8  0      <4.0            5         33              0            4         85              25    139     6         7          4.7  0      --            5         32              0            4         80              10    140     5         15         4.5  5      --            4         89              20    141     5         33         4.7  0      --            4         88              5    142     8         15         6.2  0      <4.0            7         10              0            6         71              5            5         93              5            4         97              40    143     7         40         6.8  0      <4.0            6         93              0            5         95              0            4         95              30    144     6         -7         5.1  0      --            5         75              0            4         94              15    145     6         21         5.3  0      --            5         70              5            4         94              5    146     7         0          6.0  0      <4.0            6         60              0            5         89              20            4         97              40    147     6         5          5.2  0      --            5         77              0            4         91              5    148     6         7          4.9  0      --            5         43              0            4         84              0    149     7         18         6.3  0      <4.0            6         69              10            5         95              25            4         97              30    150     7         0          6.6  0      <4.0            6.5       65              0            6         71              15            5         91              20            4         96              25    155     7         17         6.1  0      --            6         60              0            5         88              5            4         94              10    156     6         14         5.2  0      --            5         66              0            4         94              5    158     6         15         5.2  0      --            5         68              0            4         91              5    181     8         2          6.5  0      <4.0            7         24              0            6         73              5            5         96              5            4         97              25    182     8         11         6.4  0      --            7         25              0            6         63              0            5         92              0            4         95              5    183     7         31         6.6  0      4.9            6         82              15            5         97              35            4         100             85    184     7         -3         5.9  0      --            6         43              0            5         92              15            4         95              20    185     7         7          6.2  0      3.9            6         72              20            5         95              25            4         98              50    186     7         30         6.1  0      --            6         47              0            5         86              5            4         96              10            7         9          6.1  0      <4.0            6         65              0            5         92              0            4         96              25            7         14         5.9  0      --            6         35              0            5         88              10            4         95              15    187     7         0          5.6  0      --            6         23              0            5         80              10            4         93              10    188     7         49         7.0  0      5.1            6         89              30            4         99              70    189     6         -8         4.5  0      <4.0            5         19              0            4         79              25    190     7         24         6.3  0      --            6         65              10            5         93              0            4         96              15    191     7         42         6.8  0      <4.0            6         85              10            5         95              10            4         97              40    192     7         15         6.5  5      5.1            6         86              20            5         98              60            4         100             75    193     7         16         6.2  0      <4.0            6         64              0            5         90              20            4         96              30    194     7         19         6.3  0      <4.0            6         76              5            5         92              15            4         97              25    195     7         -3         6.1  0      4.9            6         67              5            5         96              45            4         98              90    196     7         57         --   0      4.8            6         90              15            5         95              30            4         100             85            9         1          7.1  0      5.2            8         19              0            7         54              0            6         88              15            5         98              70            4         99              90    197     6         7          5.2  0      <4.0            5         77              10            4         96              30    198     7         -2         6.4  0      5.5            6         92              15            5         100             80            4         100             90    199     8         7          7.1  0      5.1            7         67              0            6         93              20            5         98              60            4         100             75    200     7         -4         5.3  0      --            6         26              0            5         64              0            4         88              5    201     7         -6         5.6  0      4.8            6         15              0            5         93              25            4         97              95    202     8         8          6.2  0      4.4            7         18              0            6         66              5            5         95              30            4         97              65    203     6         6          4.5  0      --            5         15              0            4         82              15    204     8         4          6.8  0      4.8            7         34              0            6         84              10            5         98              55            4         98              70    205     7         83         --   10     --            6         97              65            5         100             90            4         100             95            8         12         7.2  0      6.2            7         71              15            6         99              70            5         99              90            4         99              95    206     7         11         6.2  0      <4.0            6         74              10            5         95              15            4         97              25    207     8         8          7.0  0      <4.0            7         52              0            6         92              10            5         96              10            4         96              40    208     7         39         6.8  0      <4.0            6         91              15            5         96              15            4         98              30    209     7         68         --   0      --            6         71              0            5         85              10            4         96              20            9         -1         6.7  0      --            8         22              0            7         37              0            6         70              0            5         87              0            4         96              5    210     9         -4         7.0  0      5.5            8         8               0            7         55              10            6         92              25            5         100             75            4         100             85    211     7         14         6.2  0      <4.0            6         69              0            5         90              5            4         97              40    213     7         -4         6.4  0      5.2            6         80              15            5         97              65            4         100             95    214     8         -3         6.8  0      5.8            7         33              0            6         90              25            5         100             95            4         100             100    215     7         2          6.4  0      5.1            6         88              25            5         98              50            4         100             80    216     6         -10        4.8  0      <4.0            5         37              0            4         90              45    217     7         1          6.1  0      4.3            6         73              0            5         95              20            4         97              60    218     7         8          6.5  0      5.6            6         87              20            5         100             90            4         100             95    219     7         43         6.9  5      5.9            6         96              45            5         100             90            4         100             95    220     7         -4         5.5  0      4.1            6         24              0            5         76              15            4         97              55    221     4         2          --   0      --    222     5         3          4.4  0      --            4         79              15    225     7         9          6.5  0      <4.0            6         84              0            5         97              30            4         99              30    226     7         50         >7.0 0      47            6         91              25            5         96              35            4         99              70            9         9          7.4  0      5.4            8         32              0            7         56              0            6         91              15            5         99              70    231     6         2          5.1  0            5         71              10            4         91              20    234     7         27         6.6  0            6         89              0            5         95              5            4         97              15    235     7         64         ˜7.0                                      0      5.5            6         94              15            5         100             90            4         100             100            8         29         7.3  0      6.0            7         52              10            6         97              55            5         100             85    236     7         43         6.9  0      5.3            6         91              10            5         99              65            4         99              70    239     7         40         6.8  0      4.2            6         88              15            5         95              25            4         99              55    240     6         6          4.4  0            5         14              0            4         70              10    241     7         14         5.8  0            6         36              0            5         82              0            4         95              5    242     6         15         4.5  0            5         25              0            4         75              0    243     5         1          4.0  0            4         49              0    244     5         1          4.1  0            4         55              5    245     5         6          4.1  0            4         54              0    246     5         11         4.5  0      <4.0            4         90              45    251     6         0          5.1  0            5         68              5            4         82              10    252     7         38         6.8  0      4.6            6         89              10            5         97              40            4         100             65    253     8         14         6.5  0      5.7            7         5               0            6         94              35            5         100             80            4         100             85            8         -10        6.5  0      4.9            7         6               0            6         92              0            5         100             30            4         100             100    254     7         18         6.6  0      5.5            6         92              35            5         99              75            4         100             95    255     5         99         >5.0 0      4.4            4         100             85            7         7          6.4  0      5.3            6         83              10            5         98              65            4         100             75    256     6         95         >6.0 0      5.3            5         99              75            4         100             80            8         -1         6.9  0      5.6            7         43              0            6         95              25            5         98              80    257     5         80         >5.0 15     <4.0            4         93              25            6         1          5.3  0      <4.0            5         74              0            4         85              25    258     7         18         6.6  0      5.1            6         92              25            5         99              50            4         100             85    259     7         3          6.1  0      5.1            6         66              5            5         99              65            4         100             100    260     5         6          4.3  0            4         66              0    261     6         -1         5.1  0      4.1            5         72              5            4         96              55    262     7         11         6.3  0      5.8            6         79              30            5         100             95            4         100             100    263     7         6          6.2  0      5.5            6         74              20            5         100             85            4         100             85    264     7         22         6.5  0      5.6            6         80              15            5         100             95            4         100             100    265     7         10         6.2  0      5.5            6         66              10            5         100             95            4         100             100    266     7         21         6.6  0      5.4            6         90              30            5         98              55            4         100             100    267     8         17         7.3  0      5.7            7         75              5            6         95              30            5         99              80            4         99              85    270     7         13         6.5  0      5.7            6         88              25            5         100             100    272     7         15         5.6  0      4.4            6         29              0            5         83              10            4         99              75    276     7         45         6.9  0      4.4            6         92              0            5         99              30            4         99              65    281     7         33         6.7  0      4.4            6         85              0            5         96              25            4         99              65    ______________________________________     FOOTNOTES     .sup.1) The rate of application is expressed as the negative log of the     molar concentration of the test compound in the diet.     .sup.2) Percent growth inhibition is derived from the total weight of     insects (IW) at each rate of application in the test relative to the tota     weight of insects in an untreated control,     ##STR259##     .sup.3) ND = No data     .sup.4) A minus % growth inhibition indicates that the insects weighed     more at the termination of the test than those in the untreated control.     .sup.5) pl.sub.50 is the negative log of the concentration of the test     chemical that provides 50% growth inhibition of the test insects.     .sup.6) Percent mortality is derived from the number of dead insects (ID)     relative to the total number of insects (TI) used in the test,     ##STR260##     .sup.7) pLC.sub.50 is the negative log of the concentration of the test     chemical that provides 50% mortality of the test insects.

                  TABLE 3    ______________________________________    Insecticidal Activity of 2,4-diaminoquinazolines    Applied as Foliar Sprays    Rate of         Percent Mortality    Cmpd No.           Application (ppm)                        TBW       BAW    CL.sup.(1)    ______________________________________    7      300          0           100          0           30           0           10           0           3            0    47     3000         80          100      85           1000         75          70       50           300          16          20       35           100          5           5        30           30           5           0        20    48     300          90          95       32           100          53          74       15           30           6           5        0           10           5           5        0    49     1000         100         100      100           300          100         100      100           100          95          100      100           30           85          35       65           10           32          5        40    50     1000         65          100      100           300          44          95       95           100          16          90       89           30           16          50       5    51     300          100         100      100           100          90          100      68           30           80          95       20           10           47          10       5    52     1000         100         100      100           300          100         100      100           100          95          100      100           30           85          90       95           10           44          20       45    53     1000         100         100      85           300          100         100      85           100          95          100      75           30           85          90       35           10           30          30       10    54     1000         100         100      100           300          100         100      95           100          55          90       35           30           32          40       28           10           5           5        11    60     1000         100         100      45           300          100         90       20           100          95          40       5           30           89          5        10           10           24          0        15    61     1000         100         100      65           300          100         100      35           100          100         85       35           30           94          70       5           10           95          10       15    63     3000         100         100      100           1000         100         100      100           300          100         100      95           100          100         95       100           30           95          85       95    66     1000         95          100      100           300          90          100      100           100          90          100      100           30           40          100      74           10           11          40       75    67     3000         17          26       25           1000         5           10       5           300          5           5        0           100          0           0        0           30           5           0        11    68     3000         0           10       10           1000         0           5        6           300          5           0        0           100          0           0        11           30           0           0        5    69     3000         5           45       25           1000         0           0        11           300          0           0        5           100          0           0        10           30           0           0        0    70     3000         0      (11) 0    (0) 10   (32)           1000         0       (0) 0    (5) 15   (25)           300          0      (10) 0    (0) 10   (20)           100          0       (0) 0    (0) 0    (20)           30           5       (0) 0    (0) 11   (21)    71     1000         5           0        15           300          0           0        21           100          0           0        10           30           0           0        5           10           5           0        15    72     3000                (70)               (80)           1000         21     (63) 0        45   (35)           300          6       (5) 0        15   (17)           100          5       (0) 0        5    (10)           30           0       (0) 0        5    (10)           10           0           0        10    73     3000         100         100      95           1000         100         100      75           300          80          90       47           100          47          50       45           30           10          5        26    74     3000         25          16       15           1000         5           0        5           300          0           0        15           100          5           0        15           30           0           0        5    80     1000         90           300          58           100          0    82     1000         100           300          95           100          90           30           39           10           7           3            0    88     1000         95           300          40           100          5    90     1000         0           300          0      (35)           100          0       (0)           30                   (0)           10                   (0)           3                    (0)    92     3000         100         10       58           1000         100         0        37           300          90          0        26           100          30          0        30           30           5           0        11    93     1000         20          0        25           300          0           0        15           100          0           0        16           30           10          0        11           10           0           0        5    107    3000         100         95       100           1000         95          78       79           300          53          21       45           100          5           5        10           30           0           10       5    108    3000         53          95       75           1000         17          50       26           300          5           5        10           100          5           0        0           30           0           0        5    109    3000         100         83       100           1000         90          59       84           300          84          10       85           100          6           16       35           30           0           0        10    111    3000         56          95       41           1000         20          35       26           300          17          5        5           100          5           0        5           30           0           0        0    112    1000         100         100      95           300          100         5        75           100          78          5        58           30           41          0        20           10           5           0        24           1000                     95           300                      63           100                      30           30                       0           10                       0    113    1000         100         100      100           300          100         100      100           100          100         95       94           30           100         29       60           10           80          5        58           100          100                  95           30           90                   83           10           37                   50           3            5                    11           1            5                    0    114    3000         100         100      100           1000         100         95       75           300          95          85       90           100          80          10       75           30           5           0        45    115    1000         100         100      100           300          100         90       85           100          95          22       90           30           89          5        85           10           29          5        25           1000                     100           300                      95           100                      50           30                       5           10                       0    116    1000         100         100      100           300          100         100      94           100          95          95       95           30           89          90       65           10           18          28       10           100          100         100      85           30           95          85       63           10           30          20       20           3            5           5        15           1            0           0        15    117    1000         100         100      100           300          100         100      90           100          95          95       90           30           75          60       84           10           40          5        58           100                               90           30                                100           10                                100           3                                 15           1                                 0    118    1000         100         100      83           300          100         95       89           100          100         35       61           30           40          21       28           10           17          0        6           100          100           30           72           10           21           3            5           1            0    121    1000         100         100      90           300          100         100      95           100          82          100      95           30           70          95       90           10           37          15       95    122    1000         100         95       71           300          83          40       44           100          53          10       5           30           16          0        6           10           0           0        0    123    1000         80          90       70           300          89          55       55           100          55          30       30           30           20          5        0           10           5           0        5    124    1000         95          85       100           300          95          37       83           100          74          5        75           30           47          0        25           10           25          0        5    125    100          95          95       100           30           95          55       95           10           37          16       28           3            5           0        5           1            0           5        0           100                               100           30                                90           10                                20           3                                 5           1                                 5    126    1000         100         95       90           300          80          79       90           100          16          5        37           30           5           0        10           10           5           0        5           300          100         70       100           100          70          5        85           30           24          0        85           10           11          0        47           3            0           0        20           100                               100           30                                95           10                                72           3                                 30           1                                 0    127    1000         85          85       100           300          65          55       65           100          45          10       50           30           5           0        15           10           0           0        0    128    1000         100         100      100           300          100         100      90           100          95          95       65           30           85          47       40           10           40          25       5    129    1000         100         100      100           300          95          95       95           100          74          50       85           30           25          5        95           10           0           0        35    131    1000         100         85       95           300          95          75       95           100          95          20       70           30           60          0        40           10           5           0        20    132    1000         100         100      100           300          100         100      84           100          95          95       95           30           80          25       90           10           25          5        15    133    1000         100         100      100           300          100         95       100           100          95          80       95           30           78          15       37           10           32          5        5    134    3000         100         100      100           1000         100         95       95           300          95          44       84           100          63          5        40           30           16          0        5    135    1000         100         15       35           300          70          0        15           100          15          0        5           30           5           0        5           10           5           10       7    136    1000         29          0        58           300          10          0        5           100          0           5        15           30           0           5        15           10           0           0        10    137    3000         50          0        42           1000         0           0        20           300          0           0        0           100          0           5        10           30           0           0        10    140    3000         74          58       20           1000         56          15       5           300          5           15       5           100          0           10       0           30           0           0        0    141    3000         16          5        0           1000         10          10       0           300          11          0        0           100          0           0        10           30           0           0        0    142    300          100         70       100           100          70          5        85           30           24          0        85           10           11          0        47           3            0           0        20           100                               100           30                                95           10                                72           3                                 30           1                                 0    143    1000         100         100      100           300          100         100      100           100          100         100      89           30           100         100      90           10           44          67       85           100          100         100      95           30           90          95       90           10           85          70       95           3            19          5        45           1            0           0        5           100                      100      100           30                       95       89           10                       79       70           3                        10       15           1                        0        0    144    3000         11          40       65           1000         10          0        55           300          0           0        5           100          0           0        10           30           0           0        5    146    1000         95          95       90           300          94          70       85           100          90          5        20           30           89          0        5           10           0           0        0    149    300          95          55       63           100          68          53       56           30           37          15       5           10           15          5        0           3            11          5        0    175    1000         89           300          35           100          10           30           5           10           0    177    300          95          100      60           100          80          95       32           30           58          60       45           10           28          5        35           3            5           0        5           300          100         100      90           100          95          95       95           30           53          90       60           10           21          6        45           3            0           5        10    178    1000         100         100      100           300          100         100      80           100          95          95       79           30           84          63       47           10           56          30       50           300                               80           100          100                  75           30           100                  90           10           90                   90           3            32                   5           1            6    179    100          100         95       100           30           65          63       95           10           53          5        40           3            5           0        10           1            0           0        0    181    1000         100         95       74           300          90          20       75           100          79          10       50           30           28          0        5           10           11          0        10    182    1000         100         90       100           300          83          32       95           100          53          5        75           30           35          0        85           10           5           0        37    183    1000         100         100      100           300          100         100      100           100          95          90       100           30           89          55       95           10           53          15       90           100          95                   80           30           84                   42           10           59                   45           3            5                    10           1            0                    5    184    1000         95          39       79           300          72          5        10           100          45          0        5           30           5           0        0           10           0           0        0    185    1000         100         100      90           300          100         89       80           100          80          55       25           30           11          15       0           10           6           16       5    186    1000         100         75       89           300          72          20       55           100          67          5        11           30           35          0        10           10           5           0        0    188    1000         100         100      100           300          100         100      100           100          100         100      100           30           95          85       84           10           71          65       55           100          100         100      80           30           95          95       58           10           71          37       60           3            6           5        5           1            6           0        0    189    300          5           95       70           100          0           44       20           30           0           5        11           10           11          5        0           3            5           0        10           3000         84           1000         39           300          10           100          0           30           0    190    1000         100         95       100           300          100         58       70           100          95          5        85           30           50          0        45           10           11          0        5    191    3000         100         100      100           1000         100         100      100           300          95          100      100           100          100         100      90           30           85          80       85           100          89          95       100           30           67          56       95           10           22          5        20           3            21          0        0           1            0           0        0    192    300          100         100      100           100          95          95       95           30           30          42       74           10           5           5        40           3            5           0        5    193    1000         100         100      85           300          90          95       85           100          89          83       85           30           22          90       25           10           0           10       5    194    1000         100         100      100           300          83          100      100           100          44          100      95           30           5           80       55           10           0           45       15           300          95          100      100           100          67          100      90           30           10          90       79           10           6           44       20           3            0           5        0    195    1000         95          47       15           300          61          26       20           100          11          15       15           30           0           0        10           10           0           0        5    196    3000         100         100      100           1000         100         100      100           300          100         100      80           100          100         100      65           30           83          53       75           100          95          95       95           30           80          6        35           10           5           5        11           3            0           0        0           1            6           0        5    197    1000         25          5        25           300          5           5        0           100          0           0        0           30           0           0        0           10           0           0        0           700          21          16       60           100          5           5        0           30           0           0        5           10           0           0        0           3            0           5        10    198    300          100         100      65           100          95          100      60           30           53          0        37           10           33          5        5           3            0           0        5           300                      95           100                      68           30                       11           10                       0           3                        7    199    300          100         100      95           100          100         100      67           30           95          95       58           10           68          25       30           3            6           5        0    200    3000         95          100      100           1000         79          100      95           300          50          95       79           100          5           68       75           30           0           15       60           1000                              100           300                               95           100                               95           30                                80           10                                55           100                               75           30                                75           10                                25           3                                 20           1                                 15    201    1000         95          95       55           300          53          45       45           100          5           20       25           30           0           0        5           10           5           11       10    202    30           6           0        55           3            21          0        5    204    30           65          20       100           3            10          5        25           300          100         100      90           100          94          95       73           30           89          24       85           10           40          26       80           3            5           0        25    205    100          100         95       50           30           100         75       5           10           78          5        0           3            25          0        6           1            18          0        5           300          100         100      95           100          95          100      40           30           90          85       5           10           70          32       5           3            10          5        5    206    1000         100         100      94           300          89          100      85           100          90          100      26           30           53          100      25           10           11          60       35    207    1000         100         100      100           300          100         100      100           100          100         100      100           30           94          100      95           10           63          100      22           100          100         100           30           94          100           10           40          95           3            7           13           1            5           0    208    1000         100         100      100           300          100         100      100           100          95          100      90           30           80          95       70           10           35          55       80           300          100           100          100         100      100           30           95          79       80           10           59          25       70           3            11          5        5           1            0           5        0           300                      100      100           100          100         100      95           30           95          95       65           10           90          45       76           3            19          5        16           1            11          5        10           100                      100      95           30                       89       80           10                       26       85           3                        10       5           1                        0        0    209    300          95          95       74           100          35          42       25           30           5           5        20           10           0           10       15           3            0           0        15           300          70          79       84           100          16          60       63           30           5           5        10           10           5           16       20           3            0           10       5           300          90          80       85           100          50          53       84           30           16          10       10           10           0           5        5           3            5           0        0           1            0           5        5    210    100          95          100      84           30           100         100      95           10           50          95       95           3            21          50       70           1            5           5        22           100          100         100      95           30           90          100      95           10           71          95       80           3            29          25       80           1            0           5        5    211    30           30          56       80           3            11          5        5           300          95          100      80           100          80          94       80           30           21          78       75           10           5           11       55           3            0           0        10    213    300          100         95       --           100          95          85       35           30           85          30       15           10           6           21       20           3            0           0        5           1000                              75           300                               47           100                               44           30                                10           10                                5    214    100          95          95       74           30           75          75       68           10           11          10       21           3            0           10       5           1            0           0        5    215    1000         100         100      100           300          100         100      100           100          95          95       90           30           69          65       37           10           7           10       5    216    100          0           26       15           30           0           0        5           10           6           0        5           3            5           11       10           1            0           21       21    217    1000         100         100      84           300          95          95       53           100          89          28       25           30           6           5        0           10           0           0        0    218    300          100         100      100           100          100         100      100           30           95          75       89           10           75          50       95           3            33          5        15    219    100          100         100      100           30           100         95       85           10           79          15       79           3            5           5        5           1            5           0        16    225    100          100         100      100           30           94          100      100           10           47          100      95           3            6           90       79           1            5           40       50           30                       95           10                       90           3                        90           1                        75           0.3                      15    226    100          100         95       100           30           95          55       100           10           65          58       95           3            24          45       18           1            0           15       5           100          100         100      100           30           95          100      100           10           59          100      95           3            33          95       90           1            0           47       5           30                       100           10                       100           3                        90           1                        53           0.3                      11    231    300          6           95       85           100          0           75       41           30           0           50       5           10           0           15       5           3            0           5        5    235    100          100         100      100           30           95          95       100           10           50          85       95           3            11          63       10           1            0           15       0    239    100          100         95       100           30           95          70       100           10           55          58       95           3            5           5        30           0            0           5    241    3000         100         90       100           1000         100         95       100           300          95          90       95           100          26          80       90           30           5           90       30           300                      65           100                      75           30                       90           10                       75           3                        16    251    100          0           5        5           30           0           11       0           10           0           6        0           3            0           0        0    252    100          95          95       95           30           42          50       60           10           29          5        5           3            0           6        0    253    300          100         95       100           100          89          83       95           30           74          61       80           10           5           5        5           3            0           0        0    254    100          100         89       100           30           89          95       63           10           30          32       6           3            5           10       6    255    300          100         25       95           100          80          40       30           30           35          21       30           10           11          30       11           3            5           40       0           300                      16           100                      10           30                       17           10                       11           3                        10    256    300          100         100      100           100          100         95       100           30           100         90       95           10           95          25       26           3            0           11       5    257    300          0           5        5           100          0           5        0           30           0           0        0           10           0           10       5           3            0           10       10    258    300          100         100      100           100          100         100      100           30           95          95       100           10           79          79       70           3            11          33       5    259    100          100         100      100           30           100         95       90           10           85          20       20           3            16          15       5           5            10          0    260    300                      10       50           100          5           6        0    261    300                      0        5           100          11          10       0    262    100          100         90           30           100         70           10           95          5           3            11          5           1            5           5    263    300          100         100      100           30           65          21       90           300          100         100      95           100          95          95       80           30           50          25       10           10           11          5        0           3            0           15       0    264    300          100         100      100           30           70          15       74           300          100         100      100           100          95          95       95           30           50          30       24           10           17          10       5           3            0           10       0    265    300                      79       100           100          100         56       95           300          100         100      100           100          100         80       95           30           79          30       25           10           39          11       5           3            6           15       0    266    100          100         95           30           89          65           10           24          10           3            5           0           1            0           5    267    300          100         100      100           100          95          100      100           30           95          89       90           10           50          20       11           3            6           10       5    272    300          100         75       53           100          80          5        0           30           26          5        0           10           6           5        5           3            0           0        5    276    300          100         100      100           100          100         100      100           30           95          95       95           10           72          65       29           3            11          32       5           100                      95           30                       68           10                       5           3                        11    ______________________________________     .sup.(1) TBW, BAW and Cl are, respectively, the abovedescribed tobacco     budworm, beet armyworm, and cabbage looper.

In a further embodiment of this invention, several of the intermediatesdisclosed above have, themselves, been found to be novel and usefulcompounds in the preparation of the quinazoline insecticides disclosedand claimed herein, which intermediates may be prepared by methodsdescribed as analogous to those described above or in the literature.

Included amongst these compounds are those having the followingstructure: ##STR261## wherein W is selected from hydrogen, halogen(e.g., chlorine), lower alkyl e.g., --CH₃, --CH(CH₃)₂ !, lower haloalkyl(e.g., --CF₃), and lower alkoxy (e.g., --OCH₃)

X is selected from

(a) halogen (e.g., Br, l);

(b) substituted aryl, e.g., phenyl! i.e., aryl substituted with one ormore halogens (e.g., Cl, F), lower alkyl (e.g., --CH₃), lower haloalkyl(e.g., --CF₃), lower alkoxy (e.g., --OCH₃), lower alkylthio (e.g., --SC₄H₉), lower alkylsulfonyl (e.g., --SO₂ C₂ H₅, or --SO₂ C₄ H₉), formyl,lower alkoxycarbonyl e.g., --C(═O)OCH₃ !, phenyl or phenyl substitutedwith one or more halogens (e.g., Cl, F) or lower haloalkyl (e.g.,--CF₃), phenoxy, or phenoxy substituted with one or more halogens (e.g.,Cl, F), lower haloalkoxy, lower alkoxyalkyl, carboxy, cyano, nitro,aminocarbonyl, lower alkylcarbonylamino, lower alkylsulfonylamino;

or substituted phenyl of the formula ##STR262## wherein R³ is hydrogen;alkyl (e.g., methyl, 1-methylethyl, n-pentyl, or undecyl); tri(loweralkyl)silylalkyl; (4-halophenyl) lower alkyl; pentahalophenylalkyl;pyridin-2-ylalkyl; or 2-(4-alkylsulfonylphenoxy)alkyl;

(c) naphthyl;

(d) thienyl or thienyl substituted with halogen, lower alkyl, orhaloalkyl;

(e) an alkenyl or alkynyl of the formulae: ##STR263## wherein G ishydrogen, trimethylsilyl or ##STR264## wherein V¹, W¹, X¹, Y¹, and Z¹are independently selected from hydrogen, halogen, lower alkyl, lowerhaloalkyl, cyano, carboxy, lower alkoxycarbonyl and aminocarbonyl; and

(f) aroyl or substituted aroyl of the formula: ##STR265## wherein V²,W², X², Y², and Z² are independently selected from hydrogen, halogen,haloalkyl, cyano, carboxy, lower alkoxycarbonyl, and phenyl substitutedwith halogen or haloalkyl;

(g) substituted aryloxy e.g., phenoxy! of the formula: ##STR266##wherein V⁴, W⁴, X⁴, Y⁴, and Z⁴ are selected from hydrogen, halogen(e.g., Cl), or haloalkyl (e.g., --CF₃)

(h) a benzo-fused oxygen-containing heterocycle of the formula:##STR267## wherein A and B are independently selected from oxygen,methylene, or carbonyl; with the proviso that at least one of A or B isoxygen; and wherein D is hydrogen, halogen (e.g., Cl, F), lower alkyl(e.g., --CH₃), or lower haloalkyl (e.g., --CF₃); and E is hydrogen,hydroxy, or lower alkoxy (e.g., --OCH₃);

Y is hydrogen or fluorine;

Z is hydrogen;

with the proviso that when X is iodo, W is other than hydrogen; when Xis bromo, W is other than hydrogen or methyl; and with the furtherproviso that when X is substituted phenyl or aryloxy, W is other thanhydrogen.

Also included amongst these compounds are those having the followingstructure: ##STR268## wherein A and B are independently selected fromoxygen, methylene, or carbonyl; with the proviso that at least one of Aor B is oxygen;

D is halogen (e.g., Cl, F), lower alkyl (e.g., --CH₃), or lowerhaloalkyl (e.g., --CF₃);

E is hydrogen, methoxy, hydroxy, amino, nitro, cyano, or aminocarbonyl;

J is hydrogen, halogen (e.g., Br, l), --B(OH)₂, or trialkylstannyl(e.g., trimethylstannyl); and,

M is lower alkyl (e.g., methyl).

These novel intermediates may readily be prepared from known startingmaterials by conventional means. Illustrations of these intermediates ofstructure I-A, and their preparation, include2-amino-5-iodo-6-methylbenzonitrile,2-amino-5-(trimethylsilylethynyl)-6-methyl-benzonitrile,2-amino-5-ethynyl-6-methylbenzonitrile, 2-amino-6-methyl-5-(4-trifluoromethylphenyl)ethynyl!benzonitrile (see Example 17);2-amino-5-bromo-6-(1-methylethyl)benzonitrile,2-amino-6-(1-methylethyl)-5- 3,5-di(trifluoromethyl)phenyl!benzonitrile(see Example 26); 2-amino-6-methyl-5-3,5-di(trifluoromethyl)phenyl!benzonitrile (see Example 1);2-amino-6-methyl-5-(5-chlorothien-2-yl)benzonitrile (see Example 18);2-amino-5-(4-trifluomethylphenylcarbonyl)-6-methylbenzonitrile (seeExample 19);2-amino-6-methyl-5-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)benzonitrile(see Example 23); and 2-amino-4-fluoro-6-methyl-5-3,5-di(trifluoromethyl)phenyl!benzonitrile (see Example 24); as well asthose of Examples 6, 16, 20-22, and 30-33.

Illustrations of these intermediates of structure l-B, and theirpreparation, include6-chloro-7-cyano-2,3-dihydro-2,2-dimethylbenzofuran,7-aminocarbonyl-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran,7-amino-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran,7-amino-4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran,4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran,6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-ylboronic acid (seeExample 23); 2,3-dihydro-2,2,6-trimethyl-7-nitrobenzofuran,7-amino-2,3-dihydro-2,2,6-trimethylbenzofuran,7-amino-4-bromo-2,3-dihydro-2,2,6-trimethylbenzofuran, and2,3-dihydro-2,2,6-trimethylbenzofuran-4-ylboronic acid (see Example 30);as well as those of Examples 27, 31, and 33.

Conversion of these intermediates to the insecticides of this inventionalso employs methods well-known to those skilled in the art, and in anyevent these methods are fully documented by the processes of the aboveexamples.

In each of these methods the nature of the substituents on the finalproduct may readily be determined by selection of the correspondinglysubstituted starting materials as shown in the examples above, or byintroduction of such groups by means well known to those skilled in theart such as conventional halogenation, reduction reactions or the like.

We claim:
 1. A compound having the formula ##STR269## wherein R¹ ishydrogen, or lower alkyl;R⁶ is hydrogen; R² and R⁷ are independentlyhydrogen, lower alkyl, alkylcarbonyl, lower alkoxycarbonyl, lowerhaloalkylcarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxyalkylcarbonyl, oralkoxyalkoxyalkoxyalkylcarbonyl; or R¹ and R², taken together, form thegroup --R⁵ --O--R⁵, wherein R⁵ is lower alkylene; W is selected fromhydrogen, halogen, lower alkyl, lower haloalkyl, phenyl, and phenylsubstituted with lower alkyl or lower haloalkyl, with the proviso thatwhen X is phenyl, W is other than hydrogen; Y and Z are selected fromhydrogen, halogen, and phenyl; and X is selected from(a) phenyl; (b)substituted aryl, wherein the substituents are selected from one or moreof halogens, lower alkyl, lower haloalkyl, lower alkoxy, loweralkylthio, lower alkylsulfonyl, formyl, lower alkoxycarbonyl, phenyl orphenyl substituted with one or more halogens or lower haloalkyl,phenoxy, or phenoxy substituted with one or more halogens, lowerhaloalkoxy, lower alkoxyalkyl, carboxy, cyano, nitro, aminocarbonyl,lower alkylcarbonylamino, lower alkylsulfonylamino; or substitutedphenyl of the formula ##STR270## wherein R³ is hydrogen; alkyl;tri(lower alkyl)silylalkyl; (4-halophenyl)lower alkyl;pentahalophenylalkyl; pyridin-2-ylalkyl; or2-(4-alkylsulfonylphenoxy)ethyl;(c) naphthyl; (d) thienyl or thienylsubstituted with halogen, lower alkyl, or haloalkyl; (e) aroyl orsubstituted aroyl of the formula: ##STR271## wherein V², W², X², Y², andZ² are independently selected from hydrogen, halogen, haloalkyl, cyano,carboxy, lower alkoxycarbonyl, and phenyl substituted with halogen orhaloalkyl; (f) (aryl)(halo)alkenyl of the formula: ##STR272## whereinV¹, W¹, X¹, Y¹, and Z¹ are independently selected from hydrogen,halogen, lower alkyl, lower haloalkyl, cyano, carboxy, loweralkoxycarbonyl, and aminocarbonyl; and (g) a benzo-fusedoxygen-containing heterocycle of the formula: ##STR273## wherein A and Bare independently selected from oxygen, methylene, and carbonyl; withthe proviso that at least one of A or B is oxygen; D is hydrogen,halogen, lower alkyl, or lower haloalkyl; and E is hydrogen, hydroxy, orlower alkoxy; to form the corresponding heterocycle2,3-dihydro-2,2-dimethylbenzofuran-4-yl,2,3-dihydro-2,2-dimethylbenzofuran-7-yl,6-halo-2,3-dihydro-2,2-dimethylbenzofuran-4-yl,5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-yl, or2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl.
 2. The compound of claim 1wherein R¹, R², R⁶, R⁷, Y and Z are hydrogen; W is methyl; andX is(i)phenyl substituted with one or more of fluoro, chloro, ortrifluoromethyl; (ii) compounds of the formula ##STR274## wherein V¹,W¹, X¹, Y¹, and Z¹ are independently selected from hydrogen, chloro, andtrifluoromethyl; or (iii) a benzo-fused oxygen containing heterocycle ofthe formula: ##STR275## wherein A and B are independently selected fromoxygen, methylene, and carbonyl; with the proviso that at least one of Aor B is oxygen; D is hydrogen, halogen, lower alkyl, or lower haloalkyl;and E is hydrogen, hydroxy, or lower alkoxy; to form the correspondingheterocycle 2,3-dihydro-2,2-dimethylbenzofuran-4-yl,2,3-dihydro-2,2-dimethylbenzofuran-7-yl,6-halo-2,3-dihydro-2,2-dimethylbenzofuran-4-yl,5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-yl, or2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl.